Danger Mouse told the Observer Music Monthly March 2008: "'Who's Gonna Save My Soul' is more of a cinematic thing to me. It felt like more of a scene in a movie that the music was taken from."
The Observer Music Monthly asked Gnarls Barkley lyricist Cee-Lo about the lines in this song, "Got some bad news this morning which in turn made my day. Oh, how could this be, all this time I've lived vicariously." He replied: "I guess that's an ode to a fallen hero - how we all either live vicariously through a father or an athlete or a musician or so on. You're left with the responsibility of planting your own flag. It's basically what the last line - 'tired enough to lay my own soul down' - means. And this is all I'll ever explain for this song, but it means that I'll do my own music now. Because this was a musician that I looked up to that either passed on or got worse or got older and less interested or interesting. I thought, 'Well, maybe he's done enough. But I haven't even started yet - so I can lay my own soul down.'"
According to Mojo magazine, Danger Mouse presented this track in demo form to Cee-Lo in a Venice hotel room, with the singer mulling over lyrics before recording it at a Cincinnati studio at a later tour stop.
The song's video was directed by Chris Milk, who previously helmed the band's Grammy-nominated promo for their cover of the Violent Femmes' "Gone Daddy Gone
Cee-Lo told Billboard magazine that this song was written about James Brown, "from an admirer's perspective... someone who had truly personified everything that we are."
The origin of this song was a 2006 James Brown concert in London, which the duo were offered the chance to attend by Brown's manager. However they were playing their own show the same night and the timing didn't work out, and the Godfather of Soul died a few months later. Cee-Lo explained to Billboard: "It disappointed me so bad. It was almost like he was about to pass a torch to me. It's my assumption but that's also my aspiration. When I say, 'I lay my own soul down,' it's like, I will have to be my own hero. I will have to save my own soul. Therefore, it is very painful, but there's also a silver lining."
Danger Mouse added: "This song really showed that we had other places to go and things to do. We tried it a couple different ways, and each time it still had a really great impact."