The circadian clock aligns behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. This review discusses the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes, and their implications for therapeutic approaches. The circadian clock in mammals is expressed in the suprachiasmatic nucleus (SCN), which maintains proper phase alignment of peripheral tissue clocks. The SCN provides 'standard time' for all peripheral tissue clocks. In experimental models, clock disruption leads to disorders in glucose metabolism, confirming the role of these genes as key regulators of metabolism. Accumulating evidence shows that multiple clock genes participate in metabolic homeostasis, suggesting that these proteins have evolved overlapping functions both as intrinsic "hands" of the clock and as regulators of metabolism. In humans, emerging studies suggest parallels in the role of circadian genes and metabolic homeostasis. Epidemiological studies indicate that increased activity during what was 'rest' time in the pre-modern world, together with sleep disruption, have been associated with increased prevalence of obesity, diabetes, and cardiovascular disease. This review highlights advances in understanding the molecular coupling between metabolic and clock networks, and its relevance to gene-environment and brain-behavioral systems important in energy balance and metabolic disease. The core clock consists of a transcription-translation feedback loop composed of transcriptional activators and repressors. Post-translational regulation by casein kinases and AMP kinase modulates the clock. Non-transcriptional mechanisms may also generate circadian oscillations. In cyanobacteria, protein phosphorylation is sufficient to generate biological rhythms. In the mammalian SCN, changes in cyclic AMP levels alter period length, an example of post-translational signaling as a mechanism controlling circadian cycles. Recent work shows that the SCN neuronal coupling network itself has intrinsic oscillatory function. Nuclear hormone receptors (NHRs) and the phase alignment of metabolic gene expression cycles are discussed. Direct evidence for metabolic input into the core clock includes the finding that the orphan nuclear hormone receptor reverse-erb alpha (REV-ERBα) and retinoic acid orphan receptors (RORα and β) constitute a short feedback loop controlling Bmal1 transcription. PPARα and the coactivator PGC1α also modulate Bmal1 transcription through this feedback loop, indicating that REV-ERBα is a nodal point for metabolic input into the clock. The interplay between the clock and metabolic transcription networks is discussed, including the direct and indirect roles of clock transcription factors in metabolic gene regulation. The reciprocal control of clock by metabolic signaling is also explored. NHRs may modThe circadian clock aligns behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. This review discusses the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes, and their implications for therapeutic approaches. The circadian clock in mammals is expressed in the suprachiasmatic nucleus (SCN), which maintains proper phase alignment of peripheral tissue clocks. The SCN provides 'standard time' for all peripheral tissue clocks. In experimental models, clock disruption leads to disorders in glucose metabolism, confirming the role of these genes as key regulators of metabolism. Accumulating evidence shows that multiple clock genes participate in metabolic homeostasis, suggesting that these proteins have evolved overlapping functions both as intrinsic "hands" of the clock and as regulators of metabolism. In humans, emerging studies suggest parallels in the role of circadian genes and metabolic homeostasis. Epidemiological studies indicate that increased activity during what was 'rest' time in the pre-modern world, together with sleep disruption, have been associated with increased prevalence of obesity, diabetes, and cardiovascular disease. This review highlights advances in understanding the molecular coupling between metabolic and clock networks, and its relevance to gene-environment and brain-behavioral systems important in energy balance and metabolic disease. The core clock consists of a transcription-translation feedback loop composed of transcriptional activators and repressors. Post-translational regulation by casein kinases and AMP kinase modulates the clock. Non-transcriptional mechanisms may also generate circadian oscillations. In cyanobacteria, protein phosphorylation is sufficient to generate biological rhythms. In the mammalian SCN, changes in cyclic AMP levels alter period length, an example of post-translational signaling as a mechanism controlling circadian cycles. Recent work shows that the SCN neuronal coupling network itself has intrinsic oscillatory function. Nuclear hormone receptors (NHRs) and the phase alignment of metabolic gene expression cycles are discussed. Direct evidence for metabolic input into the core clock includes the finding that the orphan nuclear hormone receptor reverse-erb alpha (REV-ERBα) and retinoic acid orphan receptors (RORα and β) constitute a short feedback loop controlling Bmal1 transcription. PPARα and the coactivator PGC1α also modulate Bmal1 transcription through this feedback loop, indicating that REV-ERBα is a nodal point for metabolic input into the clock. The interplay between the clock and metabolic transcription networks is discussed, including the direct and indirect roles of clock transcription factors in metabolic gene regulation. The reciprocal control of clock by metabolic signaling is also explored. NHRs may mod