In 1990, Atlanta, Georgia, teenager Crystal Jones put out a call for two more girls to join her in a trio to be called '2nd Nature'. Her request was eventually answered by Tionne Watkins, a native of Des Moines, Iowa, who moved to Atlanta with her family at an early age, and Lisa Lopes, a rapper who had just moved to the city from her native Philadelphia, Pennsylvania, with only a keyboard and 750 dollar.

The group eventually managed to arrange an audition with R&B singer Perri "Pebbles" Reid, who had started her own management and production company, Pebbitone. Impressed by the girls, Reid renamed the group "TLC"(an acronym for "Tender Loving Care" and also the members' initials) and arranged an audition for them with local record label La Face Records, run by Kenneth "Babyface" Edmonds and Reid's then-husband, Antonio " L.A." Reid. The latter Reid saw potential in Watkins and Lopes but felt that Jones should be replaced; within a few days, part-time Damian Dame backup dancer Rozonda Thomas was brought in to replace Jones. The girls were signed to La Face through a production deal with Pebbitone (with Perri Reid taking the role of the group's manager) (see Artist development deal) and almost immediately went into the studio with producers Reid and Edmonds, Dallas Austin, Jermaine Dupri, and Marley Marl to produce their first album.

The first TLC album, 'Ooooooohhh... On the TLC Tip', was released in February 25, 1992 by La Face. The songs on the album are a blend of funk (Watkins), hip-hop (Lopes), and R&B (Thomas), similar to the "new jack swing" sound popularized by producer Teddy Riley in the late 1980s; TLC's sound was dubbed "new jill swing". At the conclusion of the tour, TLC decided to take more control of their careers and thus informed Perri Reid that they no longer wished her to be their manager. Reid released the group from its management deal, but they remained signed to Pebbitone, and Reid continued to receive a share of their earnings.

Lopes began dating Atlanta Falcons American football player Andre Rison shortly after the release of 'Ooooooohhh... On the TLC Tip', and by 1994 the two were living together in Rison's upscale double-story home. Their relationship was allegedly filled with violent moments, and Lopes filed an assault charge against Rison on September 2, 1993. Rison denied battering her. Lopes was also battling alcoholism at the time. She had been a heavy drinker since the age of fifteen. After another fight between the couple in the early morning hours of June 9, 1994, Lopes tossed numerous pairs of Rison's newly purchased shoes into a bathtub, doused them with lighter fluid, and lit them on fire. The plexiglas bathtub quickly melted and set the structural frame of the house on fire. Lopes was arrested and indicted on charges of first-degree arson; she was sentenced to five years of probation and a $10,000 fine. Rison eventually reconciled with Lopes, and they continued dating on-and-off for most of the next few years.

During the fall of 1994, TLC re-entered the studio with Dallas Austin, Tim and Bob, Jermaine Dupri, Babyface, Organized Noize, and Sean "Puffy" Combs to record their second album, 'Crazy Sexy Cool'. Lopes was released from rehab to attend the recording sessions, but the finished album featured significantly less of her raps and vocals. The album instead focused more on the contributions from Watkins and Thomas, and had a smoother, more fluid sound, similar to the most successful single from the first album, the US #2 hit "Baby-Baby-Baby". All four singles from 'Crazy Sexy Cool' reached the top 5 of the US Hot 100, while "Creep" and "Waterfalls" peaked at no. 1, while Red Light Special reached no. 2 and "Diggin' on You" reached no. 5. "Waterfalls",

They declared debts totaling 3.5 million dollars, much of it because of Lopes's insurance payments arising from the arson incident and Watkins's medical bills, but the primary reason being that each member of the group was taking home less than $35,000 a year after paying managers, producers, expenses, and taxes. They sought to renegotiate their 1991 contract with La Face, under which they only received seven percent of the revenues from their album sales, and to dissolve their association with Pebbitone. Both Pebbitone and La Face countered that TLC simply wanted more money and were in no real financial danger, resulting in two years of legal debates before the cases were finally settled in late 1996. TLC's contract was renegotiated, their production deal with Pebbitone and Perri Reid (who had separated from her husband by this time) was rescinded, and the group appeared on the 'Waiting to Exhale' soundtrack with "This Is How It Works" and was set to re-enter the recording studio in 1997 after signing a new contract with La Face.

Preliminary work on TLC's third album, 'Fan Mail', was delayed when friction arose between the group and their main producer Dallas Austin, who was by this time dating Thomas and helping to raise their young son Tron. Austin wanted $4.2 million and creative control to work on the project, resulting in a stand-off between the producer and the artists. During this period, Thomas appeared in the independent film 'Hav Plenty', and Watkins co-starred in Hype Williams' 1998 film 'Belly' with rappers Nas and DMX. Watkins made a solo song in late 1996 called "Touch Myself". Lopes started her own Lopes Productions artist development company and signed Blaque, a TLC-like female R&B trio. She also appeared on the "Not Tonight" remix with fellow female rappers Lil' Kim, Missy "Misdemeanor" Elliott, Da Brat and Angie Martinez, which garnered a Grammy nomination for Best Rap Performance by a Duo, Band, or Group in 1998.

TLC eventually began working with other producers for the 'Fan Mail' album, until finally negotiating with Austin, who produced the bulk of 'Fan Mail' and gave the album a futuristic, more pop-based feel. 'Fan Mail' was another success for TLC, debuting at No. 1 on the Billboard 200 album sales chart and selling over 6 million copies in the U.S. The album featured the number-one hit "No Scrubs", produced by Kevin "She'kspere" Briggs, and the single "Unpretty," an alternative rock-styled song about self-love written by Watkins and Dallas Austin (another version of it sampled Dennis Edwards' 1984 hit" Don't Look Any Further"), that also reached #1 on the 'Billboard' chart.

The videos for both songs were heavily featured on MTV and BET, and three more singles received decent radio play: "Silly Ho", "I'm Good at Being Bad", and Edmonds-written ballad, "Dear Lie". Like 'Crazy Sexy Cool', 'Fan Mail' won the Grammy for Best R&B Album of 2000 and Grammy Award for Best R&B Performance by a Duo or Group with Vocals for "No Scrubs". The group went on a worldwide tour simply named Fan Mail Tour. While the first leg of the tour sold poorly and made the group lose 500,000 dollars, most of the second leg of the tour was sold out. The group had a Pay Per View special of their tour which at the time became Pay Per View's highest grossing televised special.

During and after the release of 'Fan Mail', Lopes made it known to the press on multiple occasions that she felt that she was unable to fully express herself working with TLC and Austin. Her contributions to the songs had been reduced to periodic eight- bar raps, and studio session singers such as Debra Killings often took her place on the background vocals for the groups' songs. In its November 28, 1999 issue, 'Entertainment Weekly' ran a letter from Lopes that challenged her group mates to record solo albums and let the fans judge which of the three was the most talented:

" I challenge Tionne 'Player' Watkins (T-boz) and Rozonda 'Hater' Thomas (Chilli) to an album entitled 'The Challenge'... a 3-CD set that contains three solo albums. Each (album)... will be due to the record label by October 1, 2000... I also challenge producer Dallas 'The Manipulator' Austin to produce all of the material and do it at a fraction of his normal rate. As I think about it, I'm sure La Face would not mind throwing in a $1.5 million dollar prize for the winner."

The ladies eventually settled the feud, and 'The Challenge' was never followed through. After the conclusion of the successful 'Fan Mail' tour, the ladies, however, took some time off and pursued personal interests. Lopes was the first to begin recording her solo album, 'Supernova'. In 2000, Spice Girl Melanie C released a single co-written with Lopes in the UK and Europe, called "Never Be the Same Again"; it became a hit reaching #1 in many countries.

Before the recording of their fourth album, '3D', there was a dispute between Lopes on one side and Watkins and Thomas on the other. Lopes originally wanted to withdraw from the group in order to see if they could duplicate their prior success without her contributions. Lopes eventually pursued solo stardom and recorded her first album 'Supernova', however it underperformed overseas and was never officially released in the United States. Before the album was completed, Lopes died in a car crash.

Returning from yet another hiatus after Lopes' death in a car crash in 2002 while on missionary work in Honduras, Watkins, Thomas and Austin decided that they would complete the remainder of their fourth album, to be called '3D', which also featured production from Rodney Jerkins, The Neptunes, Raphael Saadiq, Missy Elliott and Timbaland. The decision was also made that TLC would retire after the release and promotion of '3D', rather than replace Lopes and continue. Lopes had already completed her vocals for four songs; the remainder were performed by the remaining group members alone, who eulogized Lopes on a number of the tracks.

The first single for '3D' was "Girl Talk", the video for which featured Watkins and Thomas alone in live-action segments and Lopes in animated segments. Its follow-up, "Hands Up", featured only Watkins and Thomas in its video, but took place in a nightclub named Club Lopes (Lopes' production company's "eye" logo was a prominent feature on the club's walls). The album only sold two million copies in its first year of release, and "Girl Talk" was the only single to reach the U.S. top forty with a peak position of number 28; "Hands Up" never charted, and a third single, "Damaged", reached number 53.

In 2003, La Face had scheduled the release of 'Now and Forever: The Hits', a TLC greatest hits album with a new song, "Come Get Some", featuring Lil Jon and Sean P of the Young Blood Z. However, the compilation was not released domestically until June 2005, although versions of the compilation were released internationally in 2004 and the album was also available as a legal download from the i Tunes Store in November 2004. On June 21, 2005, 'Now and Forever: The Hits' was quietly released in the United States; the album debuted at number 53 with 20,000 copies sold.

On May 15, 2007, 'Now and Forever: The Video Hits' was released in the United States, after over four years of delayed release dates.

On August 20, 2007 a new greatest hits album was released in the UK called 'Crazy Sexy Hits: The Very Best of TLC', a play on the group's best selling album title 'Crazy Sexy Cool'. 'Now and Forever: The Video Hits' was also released in the UK for the first time on the same date. The album fared better than previous compilation 'Now and Forever: The Hits', peaking at #57 on the UK album chart ('Now and Forever: The Hits' made #86).

On June 25, 2004, Watkins and Thomas announced that they were pitching a reality television show where contestants would compete for a chance to record a single and perform in concert with the two of them. The show was eventually picked up for development by UPN. 'R U the Girl' with Watkins and Thomas debuted on UPN on July 27, 2005. The winner of the show would record with them on a new single and perform the track with them in a live concert finale in Atlanta. Roughly 4.1 million viewers tuned in for the season finale of 'R U The Girl' on September 20, 2005, with 20-year-old Tiffany "O'so Krispie" Baker as the winner. Despite media speculation that the winner of the series was to become a new, permanent member of TLC, Watkins and Thomas have stated never to replace Lopes with a new member.

On October 4, 2005, "I Bet", the first new Watkins and Thomas single in over two years, was released to radio and i Tunes, credited to "R U The Girl with Watkins & Thomas" with no mention of the TLC name on the package. The song was also appended to pressings of 'Now and Forever: The Hits' released after October 11, 2005. "I Bet" failed to chart in America and Europe, ending reports that Watkins and Thomas were putting the finishing touches on a repackaged 'Greatest Hits' album.

On June 24, 2008, Watkins and Thomas made a special appearance on the BET Awards. They, along with the original members of En Vogue and SWV, performed in Alicia Keys' tribute to girl groups. Watkins, Thomas, and Keys performed "Waterfalls". TLC were also presenters at the BETJ Virtual Awards on November 25, 2008.

In March 2009, Watkins and Thomas announced plans to perform together in a concert series in Japan featuring seventeen of TLC's songs.

On August 25, 2009 it was announced that Watkins and Thomas would perform together at the Justin Timberlake and Friends benefit concert at Las Vegas' Mandalay Bay Events Center on October 17, 2009. At the concert, Watkins announced that she and Thomas plan to record new material.