Sleep of sufficient duration, continuity, and intensity is necessary to promote high levels of cognitive performance during the wake period and to prevent physiological changes that may predispose individuals to many adverse health outcomes. Long-term shift working schedule and frequent transmeridian travel have become inevitable for many in the current society. These factors lead to the out-of-sync condition of the sleep timing with the internal body clock, and thus significantly contribute to many health conditions that we are facing. In addition, sleep insufficiency is prevalent due to the high demand in work, school, and many environmental factors. Our groups use human genetics to identify genes/mutations that give rise to unusual sleep behaviors in human. Mouse models carrying human mutations and mimicking human circadian and sleep traits, coupled with in vitro molecular studies, offer new insight into the underlying regulatory mechanisms for sleep schedule and sleep duration. Because of the fundamental role that sleep plays in our health, the pathways for regulating sleep are intertwined with those regulating many other functions. Thus, our approach also offers opportunities to investigate how sleep can impact other health conditions. A greater understanding of these mechanisms will not only lead to therapeutic interventions for treating jet-lag and sleep related disorders, but also shed new light on how sleep impinges other areas of health such as mood, cardiovascular function, metabolism, cancer, cognitive function, and performance.