First becoming prominent as the lead singer for the early grunge band Screaming Trees, he was also known as a member of Queens of the Stone Age and The Gutter Twins.

He was known for his baritone voice, which was described as being "as scratchy as a three-day beard yet as supple and pliable as moccasin leather" and has been compared to Tom Waits, Leonard Cohen and Nick Cave.

Following the end of Screaming Trees, he became a frequent collaborator of Queens of the Stone Age and was a full-time member between 2001 and 2005 during the Songs for the Deaf and Lullabies to Paralyze eras.

He also joined Layne Staley and Mike McCready in the band Mad Season,[5] and formed the alternative rock group The Gutter Twins with Greg Dulli in 2003, as well as contributing to releases by Moby, Bomb the Bass, Soulsavers, Tinariwen, The Twilight Singers, Manic Street Preachers, and Unkle, among others.

[12] Along with Alice in Chains, Pearl Jam, Soundgarden, Mudhoney, The Melvins, and Nirvana, Screaming Trees were part of Seattle's emerging grunge scene in the early 1990s.

[12] Uncle Anesthesia included the single "Bed of Roses", which gained considerable airtime on alternative rock radio stations.

[12] Sweet Oblivion was the band's breakout album and included the singles "Nearly Lost You", "Dollar Bill", "Shadow of the Season", and "Butterfly".

Following the Dust tour in the United States, Screaming Trees took another hiatus for Lanegan to begin his work on his third solo album, Scraps at Midnight.

[12] The band played a few surprise shows in early 2000, and then following a concert to celebrate the opening of Seattle's Experience Music Project they unexpectedly announced their official breakup.

Lanegan had intimated that the album came around following a Leadbelly project he was working on with Mark Pickerel, Kurt Cobain, and Krist Novoselic.

[17] The majority of the album was recorded with Pickerel on drums, Mike Johnson on guitar, Steve Fisk on piano and organ, and Jack Endino on bass.

[16] Taking nearly three years to make, the album came close to not seeing the light of day as Lanegan was set to throw the master tapes in a pond outside of the recording studio, only to be stopped by producer Jack Endino at the last moment.

After Staley's departure from the band, Mad Season began work on a potential second album featuring Lanegan as the primary vocalist.

The album was recorded the previous winter at Rancho de la Luna in Joshua Tree, California, and produced by long-time friend and collaborator Mike Johnson.

[16] and featured Rancho de la Luna owners Fred Drake and Dave Catching Lanegan's fourth studio album was released in 1999.

The album features covers of songs by prominent folk, R&B and punk artists such as Tim Hardin, Booker T. and the MGs, and country icon Buck Owens, as well as friend Jeffrey Lee Pierce of Gun Club.

[23] 2003 saw him appear on Greg Dulli's The Twilight Singers record Blackberry Belle, sharing lead vocal duties on the epic closing track, "Number Nine".

[24] Prior to releasing his fourth album, Mark Lanegan released the EP Here Comes That Weird Chill, which included "Methamphetamine Blues" (later to appear on Bubblegum) as well as a number of B-sides and rarities (including Captain Beefheart cover "Clear Spot") featuring collaborations with many who would feature on Bubblegum, such as Josh Homme, Dean Ween, Nick Oliveri and Chris Goss, as well as (notably) Natasha Shneider, Greg Dulli and Aldo Struyf.

On his next solo album, Bubblegum (2004), Lanegan was joined by a cadre of prominent artists, including P. J. Harvey, Josh Homme and Nick Oliveri of Queens of the Stone Age, Greg Dulli of The Afghan Whigs and Twilight Singers, Dave Catching of Rancho de la Luna , Dean Ween of Ween, and Duff McKagan and Izzy Stradlin, previously of Guns N' Roses.

[44] On August 12, 2010, Lanegan re-joined Queens of The Stone Age on stage at the Nokia Club in Los Angeles, where he sang four encore songs with the band.

The concert was put together to raise funds for Eagles of Death Metal bassist Brian O'Connor, who was diagnosed with cancer a few months prior to the event.

[45] In 2013, Lanegan appeared on their sixth album, ...Like Clockwork, co-writing the song "Fairweather Friends" and contributing background vocals to the track "If I Had a Tail".

[47] Lanegan and Campbell played four UK concerts in January 2007, with the London date being moved to a larger venue as a result of high demand for tickets.

The pair toured to promote the album, including a set at All Tomorrow's Parties, December 10–12, 2010 (Bowlie 2) curated by Belle & Sebastian and shows in Australia in 2011.

[65] In 2011, Lanegan's music was featured in a trailer and end credits for the video game Rage[66] and the soundtrack for the film The Hangover Part II.

Lanegan collaborated on a track "So Long Sin City" with Slash who recorded music for the 2011 indie film This Is Not a Movie, directed by Olallo Rubio, and starring Edward Furlong, Peter Coyote, Miguel Ferrer, and more.

[74] On Imitations, Lanegan offers contemporary songs, standards, and obscure numbers that, according to him, reveal the effect his parents' record collection had on him.

[79] In 2020, Lanegan contributed a spoken-word vocal performance to the song "The Mirror" by English rock band Hey Colossus, from their album Dances/Curses.

[80] He also wrote lyrics and recorded lead vocals for "A Drink Of Poison Water" on Spanish duo Agrio's La Murga Ep.

[97][104] Artists including Eddie Vedder,[105] Iggy Pop, Moby, Scott Lucas, Simon Bonney, John Cale,[106] Sleaford Mods, Badly Drawn Boy, Anton Newcombe, Peter Hook, Slash, Nick Cave, Nick Oliveri, and the members of Manic Street Preachers paid tribute.