The setlist was considered the weakest part of the game although it was praised for its diversity, critics believed that the widely varying genres represented would mean that players would not enjoy every song in the game.

Guitar Hero 5 is distributed with 85 songs on-disc, many being from artists that have yet to have their music featured in a rhythm video game, and more than half having been published in the last decade. Guitar Hero 5 is considered by its developers to be an expansion of the series into more 'social play', featuring modes such as Party Play, which allows players to drop in and out and change difficulty in the middle of a song without worrying about failing or losing points. Although traditionally a four-player band can have one player on each instrument, Guitar Hero 5 allows any four-player combination of these instruments to be used, such as a band composed of four drummers.

Songs can be played either by oneself, competitively with other players in several game modes, or cooperative with up to three other players in their own virtual band. Successfully hitting notes increases the player's scoring and performance meter, while missing too many notes will lower the performance meter and may cause the song to end prematurely. Players are awarded points by performing specific actions on the controllers to match notes that scroll on screen that correspond with the appropriate instrument. In the game, players use special instrument controllers to simulate the playing of lead and bass guitar, drums, and vocals for rock and other songs. Guitar Hero 5 is the fifth main title in the Guitar Hero series of rhythm games, released worldwide in September 2009 for the Xbox 360, PlayStation 2 and 3 and Wii consoles.

Clone hero full difficulty song packs