Phylogenetically, the serotonergic system is one of the oldest transmitter systems in the brain. Combining a complex and widespread innervation of most cortical and subcortical structures, with over a dozen receptor subtypes, there is a diversity of signaling opportunities and functional roles that explain the association of serotonin with many different types of psychopathological conditions. The role of the serotonergic system in mood disorders and in the predisposition for suicidal behavior are reviewed in this paper. Effects on the serotonergic system underlie the antidepressant action of many types of medications and must be integrated into a neurobiological model of mood disorders.