Sleep is classified into rapid eye movement (REM) and non-REM (NREM) phases. The centers of sleep and wakefulness are located in the anterior and posterior hypothalamus, respectively. The sleep-wake cycle is controlled by a combination of circadian and homeostatic mechanisms, and regulated by neurotransmitters such as GABA (γ-aminobutyric acid), histamine, orexin, acetylcholine, noradrenaline, serotonin, as well as adenosine. As NREM sleep enhanced by pro-inflammatory and suppressed by anti-inflammatory cytokines, immuno-endocrine system is also involved in the regulation of the sleep. Sleep in critically ill patients characterized by prolonged sleep latency, decreased sleep efficiency, decreased slow-wave and REM sleep, and fragmentation of sleep. The underlying illness and severity of acute illness, as well as the medications, standard of care, and environmental factors in the ICU can cause sleep deprivation. Improvements of patient care and environmental factors can increase the apparent sleep quality and reduce the incidence of delirium in critically ill patients.