Circadian rhythms help organisms adapt to predictable daily changes in their environment. Light resets the phase of the underlying oscillator to maintain the organism in sync with its surroundings. Light also affects the amplitude of overt rhythms. At a critical phase during the night, when phase shifts are maximal, light can reduce rhythm amplitude to nearly zero, whereas in the subjective day, when phase shifts are minimal, it can boost amplitude substantially. To explore the cellular basis for this reciprocal relationship between phase shift and amplitude change, we generated a photoentrainable, cell-based system in mammalian fibroblasts that shares several key features of suprachiasmatic nucleus light entrainment. Upon light stimulation, these cells exhibit calcium/cyclic AMP responsive element-binding (CREB) protein phosphorylation, leading to temporally gated acute induction of the Per2 gene, followed by phase-dependent changes in phase and/or amplitude of the PER2 circadian rhythm. At phases near the PER2 peak, photic stimulation causes little phase shift but enhanced rhythm amplitude. At phases near the PER2 nadir, on the other hand, the same stimuli cause large phase shifts but dampen rhythm amplitude. Real-time monitoring of PER2 oscillations in single cells reveals that changes in both synchrony and amplitude of individual oscillators underlie these phenomena.circadian rhythm ͉ melanopsin ͉ singularity C ircadian oscillators enable organisms to anticipate and synchronize their behavior and physiology to periodic changes in the environment. In mammals, the hypothalamic suprachiasmatic nucleus (SCN) functions as a master circadian pacemaker, coordinating tissue-autonomous oscillators to generate overt rhythms (1, 2). At the molecular level, circadian rhythms are generated by a transcription-translation feedback loop. In this circuit, the transcriptional activators CLOCK and BMAL1 drive expression of the Cryptochrome 1 (Cry1), Cry2, Period 1 (Per1) and Per2 genes, whose protein products, in turn, repress CLOCK/BMAL1 transcriptional activity (reviewed in ref.3). The phase of rhythms in mRNA and protein levels of these repressors, particularly Per2, reflects the phase of the oscillator (4).Light entrains the SCN pacemaker, which relays phase information to peripheral oscillators via humoral and synaptic mechanisms. The retinorecipient cells of the SCN receive direct synaptic input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) that express melanopsin. Upon photostimulation, the ipRGCs release neurotransmitters, which act via their cognate receptors to phosphorylate the calcium/cAMPresponsive element-binding protein (CREB). In turn, transcriptionally active phospho-CREB (pCREB) binds to Per1 and Per2 promoter CRE sites and activates transcription, subsequently resetting the phase of the molecular oscillator (reviewed in refs. 5 and 6). Mice bearing a targeted mutation in the CREB phosphorylation site (7) or perturbed Per function (8, 9) exhibit attenuated phase resetting.