Circadian mechanisms regulate most mammalian physiology, with particular importance in the regulation of innate immunity, through the macrophage in particular, and energy metabolism, regulating liver, adipose and muscle.  These circuits are also regulated by a number of nuclear receptors, which show a striking interdependency on the circadian machinery; some having ligand availability regulated by the clock, others varying in expression level through the day.  We have employed a range of approaches to address the physiological importance of the circadian:nuclear receptor system, ranging from population genetics, experimental medicine studies, CRISPR engineered mice, and cell biology.  These approaches have discovered how the important dimension of time regulates metabolism, and coordinates diverse tissues to deliver optimal organismal performance.  Importantly, we are identifying how external stressors can decouple these systems, with deleterious effects.