Mammalian physiology is governed by a complex circadian timing system that involves interacting positive and negative transcriptional feedback loops. A key role in this feedback loop was attributed to the PAS domain helix–loop–helix protein CLOCK, on the basis of a dominant-negative mutation in this transcription factor. However, recent experiments by Reppert and coworkers with Clock knockout mice suggest that CLOCK is dispensable for rhythmic gene expression and behavior, presumably because other proteins can substitute for CLOCK in these animals.