The Big Whiskey and the GrooGrux King album title is a reference to the band's private nickname for their sax player, LeRoi Moore, who died in the summer of 2008 following a quad-bike accident, something that shook the DMB to the core. On this ballad Moore's sax lines echo with Matthews' vocals. Matthews told Rolling Stone: "It's kind of like a duet between us. The good space that the band is in still very much includes him. Once this is done, I don't know what'll happen."
Matthews told Relix magazine the story of this song: "We worked up an arrangement as a band and then I went off to write the lyrics and the melody. I was like, 'I nailed this one!' And I came back and they pressed record while I tried to play the song. It was so slow that I couldn't sing what I had written over it. It wouldn't work. So we sped up the recording and I sang over that and it worked like a champion. So we kept all the squeezed music. Melodically, it's just so gorgeous and lush, sad and defiant… I don't want to say too much about these lyrics, but it might be my favorite lyrically of all the songs. I was singing the background vocals in Seattle, before we came down to New Orleans, and we kept a lot of those vocals. I was so tired, because it was the last night of the session, that I was leaning in a chair with a microphone right in front of the board and singing. It had a sort of sleepy sound to it that we couldn't recapture, so we kept it. 'Save yourself'—that was me at 4:30 in the morning, sick and tired."
Matthews added about the song's lyrical content: "I don't know whether it's a song about being lost or being f--kin' out of your mind because you licked some cactus or swallowed some mushroom somewhere and turned your head upside down. It could be "Hey! (hey), You! (you), Get off of my cloud." It could be a lot of things. I like songs that just create beautiful images and that's why I don't want to talk about the lyrics because I just think it's perfect. Some of the songs have to be open."