The song is about the role drugs play in the process of making music.

When asked in an interview if it is easier to make music on drugs, Josh Homme said "Well I think we have a song that about this subject called First they Giveth, then They Taketh away, and I think at first you can draw inspiration and then eventually, it negates any inspiration.

The music video for "First It Giveth" shows the band playing live at the Glastonbury Festival and on their tour with the Red Hot Chili Peppers in 2002.

It is famous among fans for showing Nick Oliveri playing naked on stage.

The B-sides, "Wake Up Screaming" and "The Most Exalted Potentate of Love", appeared subsequently on the compilation EP Stone Age Complications.