Disturbed sleep is one of the hallmark signs of depression. After successful treatment, many of these signs disappear; however, changes in rapid eye movement (REM) sleep may persist and even predict recurrence of depression. High-risk studies have established these alterations to be not only biological scars but true endophenotypes for depression. REM sleep changes are mediated by the noradrenergic, serotonergic, and cholinergic systems and are under strong genetic control. REM sleep has a crucial role for brain maturation and is inhibited during ontogeny. Lack of this inhibition may predispose an individual to depression. Findings regarding the CREB gene support REM sleep's role in depression. The combination of psychopathology and neurobiological measures, such as REM sleep parameters, will help to improve genetic studies and therefore increase the knowledge of relevant pathways for depression. This could facilitate development of preventive and therapeutic measures.