"Man in the Box", the second single from Alice in Chains' debut album, Facelift (1990), garnered Staley critical recognition for his vocal style.

He began to work on a side project with several Seattle musicians, Mike McCready of Pearl Jam, Barrett Martin of Screaming Trees, and John Baker Saunders of The Walkabouts, which came to be Mad Season, while Alice in Chains went into hiatus.

[7] During Alice in Chains' hiatus, reports of Staley's drug addiction began to gain widespread circulation in fan and media communities, in part due to changes in his physical condition brought on by prolonged heroin abuse.

Aside from recording two more songs with Alice in Chains – "Get Born Again" and "Died" – and a cover of Pink Floyd's "Another Brick in the Wall" with Class of '99 during 1998, Staley had been out of the public spotlight by the late 1990s.

[6] In 1984, Staley joined a group of Shorewood High students in a band called Sleze,[22] which also featured future members of The Dehumanizers and Second Coming.

[31][32] Cantrell agreed on condition that Staley join his band,[32] which at the time did not have a name and included drummer Sean Kinney and bassist Mike Starr.

[30] Two weeks after the band's formation, they were playing a gig at the University of Washington, trying to fill in a 40-minute set with a couple of original songs along with Hanoi Rocks and David Bowie covers.

Curtis and Silver passed the demo on to Columbia Records' A&R representative Nick Terzo, who set up an appointment with label president Don Ienner.

"Man in the Box" is widely recognized for its distinctive "wordless opening melody, where Staley's peculiar, tensed-throat vocals are matched in unison with an effects-laden guitar" followed by "portentous lines like: 'Jesus Christ/Deny your maker' and 'He who tries/Will be wasted' with Cantrell's drier, and less-urgent voice.

Eventually, Staley would receive credit for about half the lyrics from the entire Alice in Chains catalog prior to the release of Black Gives Way to Blue in 2009.

[6] Following the album's release, Staley entered a rehabilitation clinic and began to work on a side project with several Seattle musicians, Mike McCready of Pearl Jam, Barrett Martin of Screaming Trees and John Baker Saunders of The Walkabouts.

[7] The band worked on material for several months and played its first show on October 12, 1994, at the Crocodile Cafe in Seattle under the name "The Gacy Bunch".

[56] During Alice in Chains' hiatus, reports of Staley's addiction began to gain widespread circulation in fan and media communities, in part due to changes in his physical condition brought on by prolonged heroin abuse.

[6] Staley shared lead vocals with Ann Wilson for a cover of Bob Dylan's "Ring Them Bells", featured on Heart's 1993 album Desire Walks On.

[65] One of the last songs that Staley recorded was a cover of Pink Floyd's "Another Brick in the Wall" with the supergroup Class of '99, featuring guitarist Tom Morello of Rage Against the Machine, bassist Martyn LeNoble, drummer Stephen Perkins, both from Jane's Addiction and Porno for Pyros, and keyboardist Matt Serletic.

[80] In 1998, amid rumors that Staley rarely left his apartment, had contracted gangrene, and had lost the ability to ingest food and was living on a diet of Ensure, Jerry Cantrell told Kerrang!

[6] On June 22, 1998, Staley made a phone call to radio program Rockline and gave a rare interview while Cantrell was promoting his first solo album, Boggy Depot.

[84] Thereafter, Staley was thought to have left behind his "self-imposed rock & roll exile", when in November 1998 he laid down additional vocal tracks as part of a supergroup called Class of '99, featuring members of Rage Against the Machine, Jane's Addiction, and Porno for Pyros.

[66] On July 19, 1999, the radio program Rockline was hosting Cantrell, Inez, and Kinney for a discussion on the release of Nothing Safe: Best of the Box, when, unexpectedly, Staley called in to participate.

[87][88] Staley's mother, Nancy McCallum, told The Seattle Times in 2007 that despite his isolation, he was never far from the love of his family and friends, who filled his answering machine and mailbox with messages and letters.

[101] An informal memorial was held for Staley on the night of April 20, 2002, at the Seattle Center, which was attended by at least 100 fans and friends, including Alice in Chains bandmates Cantrell, Starr, Inez and Kinney, and Soundgarden frontman Chris Cornell.

[99] Staley's private memorial was attended by his family and friends, along with his Alice in Chains bandmates, the band's manager Susan Silver and her then-husband Chris Cornell, as well as other music personalities.

[114] Cold's song "The Day Seattle Died" from their 2003 album Year of the Spider was an ode to Staley, as well as fellow grunge figurehead Kurt Cobain.

[128] In 2009, Alice in Chains released their first studio album in 14 years, Black Gives Way to Blue, with Cantrell and then-new vocalist and rhythm guitarist William DuVall sharing lead vocals.

[130] Cantrell invited Elton John to join Alice in Chains and pay tribute to Staley playing the piano in "Black Gives Way to Blue",[131] the closing song in the album.

[138] In 2013, Alice in Chains' drummer, Sean Kinney, added the initials "LSMS" on his drum kit, a tribute to Staley and the band's former bassist, Mike Starr, who died in 2011.

[139][140] The music video for Alice in Chains' 2013 single, "Voices", features a picture of Staley next to a photo of Nirvana's frontman, Kurt Cobain, at the 2:20 mark.

[144][145] On what would've been Staley's 50th birthday, August 22, 2017, Alice in Chains released a video paying tribute to him, featuring Jerry Cantrell, Ann Wilson, Mike McCready, and Barrett Martin.

[146] William DuVall revealed that he was thinking about Staley, his grandmother and the Soundgarden lead vocalist Chris Cornell while writing the Alice in Chains' song "Never Fade", from their 2018 album, Rainier Fog.

[76] Staley's last interview was for the radio program Rockline on July 19, 1999, promoting the release of the compilation album Nothing Safe: Best of the Box with the other members of Alice in Chains.