Sleep is ubiquitous among mammals, essential for life, and implicated in the pathogenesis of a variety of physical and mental disorders. Studies were carried out to elucidate further its function and the consequences of its deprivation. Prolonged sleep deprivation in rats causes a negative energy balance and malnutrition symptoms, despite normal integrity of intermediary metabolic pathways as well as increased food consumption. Dietary nutrient composition, which exerted a negligible influence under normal conditions, was found to interact strongly with sleep deprivation, affecting the time-course and development of pathologies. The reason for death from sleep loss has long been unresolved despite numerous morphological, histological, clinical chemistry, and hematological analyses. We found that deprivation eventuates in a breakdown of host immune defense and invasion of the bloodstream by opportunistic, toxigenic microbes. This finding not only identified the events predisposing to death, it implicates cytokines in the mediation of pathophysiology and suggests that sleep preserves immunocompetence. The thyroid hormone profile during sleep deprivation is abnormal and unusual. TRH challenge tests resulted in suppressed plasma free T4, but normal free T3, and normal basal and stimulated TSH levels (not expected from low T4) . These findings among others indicate a rapid conversion of T4 to T3. Also, low plasma T4 without increased TSH indicates central hypothyroidism, possibly due to either TSH that is not bioactive or TRH that is suppressed secondary to increased brain temperature. The sleep-deprivation-induced increase in whole-body catabolism is not reflected in local rates of glucose utilization in the brain, which tend to be decreased. Brain temperature and brain glucose utilization become dissociated, due to either an in brain usage of alternate substrates or decreased blood flow.