In humans, most physiological and behavioural functions demonstrate a circadian rhythmicity, which is essential to adequately cope with dramatic fluctuations occurring in the external environment. Therefore, it is intuitive that alterations in the endogenous machinery regulating circadian oscillations may lead to physical and mental symptoms and morbidities. Mood disorders, especially unipolar depression and seasonal affective disorder, have been linked to circadian rhythm abnormalities. This paper provides a brief description of the molecular and genetic mechanisms regulating the endogenous clock system and reviews selected studies describing circadian abnormalities in patients with depression. Evidence is emerging that a disruption of the normal circadian rhythmicity occurs at least in a subgroup of depressed patients and that interventions able to resynchronize the human circadian system, including sleep deprivation, light therapy and drugs specifically acting on the endogenous clock system, have proven antidepressant effects. It seems likely that, in the future, the knowledge coming from the exploration of molecular and genetic mechanisms involved in the physiology of the circadian clock system will be fruitful for a deeper understanding of the etiopathogenesis of mood disorders and the development of more effective therapeutic strategies.