The physiological significance of a peripheral tissue circadian clock is highlighted in this study, which demonstrates that the liver clock plays a critical role in glucose homeostasis. Mice with a liver-specific deletion of Bmal1, a key component of the circadian clock, exhibited hypoglycemia during the fasting phase of the daily feeding cycle, exaggerated glucose clearance, and loss of rhythmic expression of hepatic glucose regulatory genes. These findings suggest that the liver clock is important for buffering circulating glucose in a time-of-day-dependent manner. The liver clock contributes to homeostasis by driving a daily rhythm of hepatic glucose export that counterbalances the daily cycle of glucose ingestion resulting from the fasting-feeding cycle. Circadian clocks are intrinsic daily rhythms of physiology and behavior driven by cell-autonomous oscillators. In mammals, the suprachiasmatic nucleus (SCN) acts as the central pacemaker, while peripheral clocks are set by daily feeding. The liver, a well-known player in glucose homeostasis, has circadian-regulated genes involved in glucose metabolism. Mice with a liver-specific disruption of Bmal1 showed impaired gluconeogenesis, indicating the liver clock's role in hepatic glucose metabolism. However, the SCN may also regulate hepatic glucose metabolism through autonomic projections. The study used mice with a liver-specific loss of circadian clock function to investigate the physiological functions of the liver clock. These mice showed hypoglycemia during fasting and exaggerated glucose clearance, suggesting a defect in hepatic glucose export. The liver clock is likely important for additional aspects of liver physiology, such as xenobiotic clearance. The findings provide direct evidence that a circadian clock in a peripheral tissue has a significant physiological function in vivo. The presence of circadian rest-activity cycles in animals from insects to mammals suggests that daily rhythmic organization of behavior has provided a strong selective advantage, but the resultant daily rhythms of food ingestion and energy expenditure likely result in major challenges for systemic homeostasis. Peripheral tissue circadian clocks may have been selected over evolutionary time to drive rhythms of physiological processes that counteract undesirable physiological consequences of daily behavioral rhythms.The physiological significance of a peripheral tissue circadian clock is highlighted in this study, which demonstrates that the liver clock plays a critical role in glucose homeostasis. Mice with a liver-specific deletion of Bmal1, a key component of the circadian clock, exhibited hypoglycemia during the fasting phase of the daily feeding cycle, exaggerated glucose clearance, and loss of rhythmic expression of hepatic glucose regulatory genes. These findings suggest that the liver clock is important for buffering circulating glucose in a time-of-day-dependent manner. The liver clock contributes to homeostasis by driving a daily rhythm of hepatic glucose export that counterbalances the daily cycle of glucose ingestion resulting from the fasting-feeding cycle. Circadian clocks are intrinsic daily rhythms of physiology and behavior driven by cell-autonomous oscillators. In mammals, the suprachiasmatic nucleus (SCN) acts as the central pacemaker, while peripheral clocks are set by daily feeding. The liver, a well-known player in glucose homeostasis, has circadian-regulated genes involved in glucose metabolism. Mice with a liver-specific disruption of Bmal1 showed impaired gluconeogenesis, indicating the liver clock's role in hepatic glucose metabolism. However, the SCN may also regulate hepatic glucose metabolism through autonomic projections. The study used mice with a liver-specific loss of circadian clock function to investigate the physiological functions of the liver clock. These mice showed hypoglycemia during fasting and exaggerated glucose clearance, suggesting a defect in hepatic glucose export. The liver clock is likely important for additional aspects of liver physiology, such as xenobiotic clearance. The findings provide direct evidence that a circadian clock in a peripheral tissue has a significant physiological function in vivo. The presence of circadian rest-activity cycles in animals from insects to mammals suggests that daily rhythmic organization of behavior has provided a strong selective advantage, but the resultant daily rhythms of food ingestion and energy expenditure likely result in major challenges for systemic homeostasis. Peripheral tissue circadian clocks may have been selected over evolutionary time to drive rhythms of physiological processes that counteract undesirable physiological consequences of daily behavioral rhythms.