Recent transcript profiling and microarray studies are beginning to unveil some of the mysteries of sleep. One of the most important clues has been the identification of the endoplasmic reticulum (ER) resident chaperone, immunoglobulin binding protein (BiP), that increases with sleep deprivation in all species studied. BiP, an ER resident chaperone, is the key cellular marker and master regulator of a signaling pathway called the ER stress response or unfolded protein response. The ER stress response occurs in 3 phases. It is healthy, protective and adaptive when the ER stress is moderate. Failure of the adaptive response leads to the activation of an inflammatory response. When the ER stress burden is great and prolonged, executioner pathways are activated. Collectively this work provides new evidence that modest sleep deprivation induces cellular stress that activates an adaptive response. Aging tilts the response to sleep deprivation from one that is adaptive and protective to one that is maladaptive. Understanding the pathways activated by sleep loss and the mechanisms by which they occur will allow the development of therapies to protect the brain during prolonged wakefulness and specifically in sleep disorders including those associated with aging.