In modern societies, the risk of developing metabolic disorders such as obesity or type-2 diabetes is associated with the prevalence of psychosocial stress. Therefore, an improved understanding of adaptive stress responses and their underlying molecular mechanisms is of high clinical interest. In response to an acute stressor, animals activate the sympathetic nervous system and the hypothalamuspituitaryadrenal (HPA) axis releasing catecholamines and glucocorticoids (GCs) into the circulation. Recent data suggest that stress responses are also regulated by the endogenous circadian clock adapting physiology and behavior to the environmental changes brought about by the Earths rotation around its axis. Thus, the timing of stress may critically affect adaptive responses to and the pathological effects of repetitive stressor exposure. We have studied the role of different tissue clocks on the regulation of HPA axis activity in mice. We further characterized the impact of predictable social defeat stress during daytime versus nighttime on metabolic regulation and HPA axis activity. Repeated nighttime stressor exposure led to alterations in food metabolization and reduced HPA axis activity with lower circulating adrenocorticotropic hormone (ACTH) and GC concentrations at the time of predicted stressor exposure. Together, our data suggest a circadian gating of stress adaptation at the level of the HPA axis with impact on metabolic homeostasis.