Despite its clinical and socio-economic relevance, surprisingly little is known on the etiology of depression. A multitude of neurobiological and psychosocial hypotheses have been postulated but most lack empirical validity or cannot be integrated into comprehensive pathophysiological models. In neurobiological research, most evidence supports a contribution of genetic factors in the causation of depression. However, it seems that only the susceptibility for the disorder is inherited which ultimately causes the onset of depressive symptoms by interacting with psychosocial adversity. More recent research suggests an important role for altered stress responses and disturbed neuroplasticity in the etiopathogenesis of depression. From a psychosocial point of view, the different approaches prioritize different aspects. Psychoanalytical approaches assume a fragile self-worth system developed in early childhood as a decisive vulnerability factor for later depression. Behavioral-cognitive theories focus on dysfunctional cognitions coupled with learned helplessness and behavioural deficits as well as a failing in positive reinforced activities as predisposing factors for affective disorders. Interpersonal theories, however, postulate that the psychosocial and interpersonal context is most important for the development and course of depression. With regard to the etiopathogenesis of the so called difficult-to-treat chronic depression, especially early traumata as well as preoperational patterns of thinking seem to play a decisive role. In conclusion, only bio-psycho-social models which integrate neurobiological and psychosocial vulnerabilities and stressors have the potential to contribute to a better understanding of the etiology of depression.