Mood disorders are amongst the most prevalent and severe disorders worldwide, with a tendency to be recurrent and disabling. Although multiple mechanisms have been hypothesized to be involved in their pathogenesis, just a few integrative theoretical frameworks have been proposed and have yet to integrate comprehensively all available findings. As such, a comprehensive framework would be quite useful from a clinical and therapeutic point of view in order to identify elements to evaluate and target in the clinical practice. Because conditions of sleep loss, which include reduced sleep duration and insomnia, are constant alterations in mood disorders, the aim of this paper was to review the literature on their potential role in the pathogenesis of mood disorders and to propose a novel theoretical model. According to this hypothesis, sleep should be considered the main regulator of several systems and processes whose dysregulation is involved in the pathogenesis of mood disorders. The model may help explain why sleep disturbances are so strikingly linked to mood disorders, and underscores the need to evaluate, assess and target sleep disturbances in clinical practice, as a priority, in order to prevent and treat mood disorders.