Several discoveries point to the importance of the molecular clockworks as an integrative system in biology. The molecular clock is highly conserved and remarkably robust in resisting disruption; it is highly regulated and is placed centrally amongst biological networks that communicate between tissues. In recent years it has become apparent that peripheral clocks, widely distributed, retain the capacity for independence as well as operating under the direction of the master clock in the supracharismatic nucleus (SCN). Indeed, evidence has begun to emerge that peripheral clocks talk to each other and back to the SCN. As we begin to understand the impact of major environmental influences, such as food restriction and fluctuations in body temperature, on clock integration and behavior, so we will begin to elucidate the roles of fine adjusters, such as hormones, physical forces and nutritional ingredients, all of which can impact asymmetrically individual peripheral clocks and potentially signal between them. Much remains to be learned about the multiple levels of regulation of clockworks at the transcriptional, translational, post translational and epigenomic levels, information that lends itself to systems wide analysis. Indeed, increasing insight into the systems biology of the molecular clock promises to rationalize selection of drug targets whereby we might modulate clock function. High throughput screens have already yielded novel approaches to regulating the phase and amplitude of molecular clocks. Evocation of clock dependent phenotypes in humans has come of age with recognition that the oscillatory nature of the metabolome and the ability to track gene oscillations in several tissues ex vivo will complement increasingly sophisticated approaches to segregating endogenous rhythms from tracking time dependent changes in tissue function in humans. Experiments in a range of model systems have pointed to the importance of the molecular clock in carbohydrate and lipid metabolism, cardiovascular function and aging. This program will assemble investigators who work in multiple model systems, including humans to share information on the multiple ways in which the molecular clock is regulated, how its systems are integrated and how that knowledge might be harvested to enhance our understanding of human physiology and to yield novel treatments for human disease.