- In mammals, the circadian timekeeping system consists of multiple, cell-autonomous clocks that are prevalent throughout the body. The suprachiasmatic nucleus (SCN) of the hypothalamus is the master clock that links environmental time cues to local processes. Peripheral tissues and other brain regions also harbor molecular components of the circadian timekeeping mechanism found in the SCN and these clockworks provide for the organization of tissue- or cell-specific activities in time. Despite the widespread distribution of the canonical clockworks, only the SCN is capable of pacing the oscillations of circadian clocks in other cells and tissues. Output signals responsible for the coupling between cell-autonomous clocks in the SCN and/or the coordination of circadian oscillations in peripheral clocks may be specific to the SCN and necessary for its circadian pacemaker function. These critical outputs of the SCN circadian pacemaker are diffusible or humoral factors. Several SCN outputs essential for the circadian regulation of wheel-running behavior have been identified, but the diffusible signals responsible for pacing other circadian oscillations are unknown. 2009 Elsevier Ltd All rights reserved.