Forward genetic analyses in flies and mice have uncovered conserved transcriptional feedback loops at the heart of circadian pacemakers. Conserved mechanisms of posttranslational regulation, most notably phosphorylation, appear to be important for timing feedback. Transcript analyses have indicated that circadian clocks are not restricted to neurons but are found in several tissues. Comparisons between flies and mice highlight important differences in molecular circuitry and circadian organization. Future studies of pacemaker mechanisms and their control of physiology and behavior will likely continue to rely on forward genetics.