Transcriptional feedback loops are at the heart of circadian clocks of mammals and other organisms, but evidence is emerging that suggests that other signaling mechanisms also have important roles in basic functions of the clock. O’Neill et al. (see the Perspective by Harrisingh and Nitabach) show that cytosolic signaling through adenosine 3′,5′-monophosphate (cAMP) integrates with the transcriptional timing mechanism, sustains it, and determines the fundamental properties (amplitude, phase, and period) of the transcriptional feedback loops of the mammalian circadian pacemaker. This expands the paradigm of cellular circadian oscillation control by transcriptional feedback loops to include small-molecule cytoplasmic signals that differ between species--cAMP in mammals, Ca 2+ in mammals and insects, and cyclic ADP ribose in plants. J. S. O'Neill, E. S. Maywood, J. E. Chesham, J. S. Takahashi, M. H. Hastings, cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 320 , 949-953 (2008). [Abstract] [Full Text] M. C. Harrisingh, M. N. Nitabach, Integrating circadian timekeeping with cellular physiology. Science 320 , 879-880 (2008). [Summary] [Full Text]