Sleep is essential for mammals and possibly for all animals. Advancing our knowledge of sleep regulation is crucial for the development of interventions in sleep-related health and social problems. With this aim, this study utilizes laboratory mice to explore sleep regulatory mechanisms at behavioral, molecular, and genetic levels. Sleep is regulated by the interaction of circadian and homeostatic processes. The circadian clock facilitates sleep to occur at a favorable time of the day. Normal mice, such as the C57BL/6J (B6) strain, sleep mostly during the day and initiate activities at dark onset. Here, I show mice of the CAST/EiJ (CAST) strain initiate activity unusually early (hours before dark). The circadian gating of photic phase-shifting responses was phase-lagged in the CAST mice relative to their activity rhythms, implying an altered coupling between the clock and its output. Light failed to suppress activity in the CAST mice, allowing full expression of the early activity. A previously identified quantitative trait locus that contributes to the advanced circadian phase was also confirmed and refined to a smaller genomic region. The circadian oscillation and light-induction of clock-genes Per1 and Per2 expression was not different between B6 and CAST mice in the suprachiasmatic nucleus (SCN) of the brain, where the mammalian master circadian clock is located. However, in the cerebral cortex and paraventricular hypothalamic nucleus of CAST mice, Per mRNA oscillations were phase-advanced coordinately with their advanced behavioral rhythms. These data thus provide direct evidence that the cause of the early runner phenotype is located downstream of the master circadian clock. The rhythms of cortical Per expression may not be a result of direct SCN effector mechanisms, but rather driven by activity-rest and sleep-wake. I further show that prolonged waking induces cortical Per expression, and this induction persisted in SCN-lesioned animals. SCN Per expression in intact animals was not affected. Thus, a homeostatic drive, independent of the SCN clock, regulates cortical Per expression, although a possible circadian influence in the intact animals was also suggested by detailed analyses. These data may suggest a molecular mechanism bridging the circadian and homeostatic processes for sleep regulation and functions.