The present review synthetically describes the currently advanced hypotheses for a neurobiological basis of depression, ranging from the classical monoaminergic to the more recent neurotrophic hypothesis. Moreover, the Authors review the available preclinical and clinical evidence suggesting a possible role for the endocannabinoid system in the physiopathology of depression. Indeed, in spite of the reporting of conflicting results, the pharmacological enhancement of endocannabinoid activity at the CB1 cannabinoid receptor level appears to exert an antidepressant-like effect in some animal models of depression. On the contrary, a reduced activity of the endogenous cannabinoid system seems to be associated with the animal model of depression, namely the chronic mild stress model. Moreover, a few studies have reported an interaction of antidepressants with the endocannabinoid system. With regard to clinical studies, several authors have reported an alteration of endocannabinoid serum levels in depression, while post mortem studies have demonstrated increased levels of endocannabinoids associated to a concomitant hyperactivity of CB1 receptor in the prefrontal cortex of suicide victims. No clinical trials carried out using cannabinoids in the treatment of affective disorders have been published to date, although anecdotal reports have described both antidepressant and antimanic properties of cannabis as well as the ability of cannabis to induce mania that has also been documented. These findings are discussed, leading us to conclude that, although data available are sufficient to suggest a possible involvement of the endogenous cannabinoid system in the neurobiology of depression, additional studies should be performed in order to better elucidate the role of this system in the physiopathology of depression.