Greatest Hits is the second collection of hit songs by the band, albeit shorter than the previous release, Nothing Safe: Best of the Box. Greatest Hits was certified gold by the RIAA on November 30, 2005.
It was the last album released by Alice in Chains before the death of singer Layne Staley in 2002. Mike Starr plays bass on the album's first five songs, while Mike Inez plays bass on the last five.
The album featured two covers. The first cover features a photo of retired boxer Gene Fullmer receiving a crushing right from Neal Rivers. The unofficial second cover features the members of the band's heads on a rainbow background without the text on the cover.
The album received a mixed reception from critics, with reviewers criticizing the lack of songs and "Cash grab" nature of the album. Allmusic's Steve Huey called the album "a lower-priced, ten-track sampler of Alice in Chains' career." Bill Adams of Ground Control Magazine questioned the integrity of the album, writing in his review "one has to wonder who this compilation was made for. When it was released in 2001, Alice in Chains had only gone for about six years without a new studio album, and fans had been kept interested with live albums, box sets and myriad other releases, so why put out something so plainly utilitarian?".