Sleep deprivation (SD) is a powerful antidepressant treatment that shows antidepressant responses within hours in 40-60% of depressed patients. In more than 80% of responders to SD, a relapse into depression occurred after the recovery night. In addition, it serves as an excellent tool to examine the neurobiological disturbance of depression and may profoundly contribute to the development of new specific and more rapidly acting antidepressants. The reason why SD works and relapses occur is still unclear. A key to solve this problem is to include the current knowledge about the neurobiological disturbance of depression in research, with a focus on neurobiological aspects of sleep and SD (sleep EEG, neuroendocrinology, neurochemistry and chronobiology). Based on findings from these different areas, different strategies to stabilize the antidepressant effect of SD have been applied. This article provides an overview of clinical and neurobiological responses related to SD in depression.