Affective disorders comprise mood disorders such as unipolar depression and anxiety disorders, including generalized anxiety, post-traumatic stress disorder, panic, phobia and obsessive-compulsive disorder. The etiology of these disorders is related to stress. Further, they are characterized by alterations of the hypothalamus-pituitary-adrenal (HPA) axis function, controlling the endocrine response to stress. Vasopressin is a nonapeptide that is mainly expressed and/or released in the hypothalamus and the pituitary, but also in other brain areas particularly in limbic regions. It strongly contributes to the endocrine and neural response to stress. Therefore, it has been suggested that vasopressin may be involved in affective disorders. Here, we review both clinical and preclinical data that investigated this hypothesis. Several studies show an increased plasmatic level of vasopressin in anxiety disorders as well as in unipolar depression. Further, a single nucleotide polymorphism (SNP) of the vasopressin V(1b) receptor has been found to protect against depression. Preclinical data are convergent with the clinical findings. For example, Brattleboro rats, that display decreased vasopressin function, show reduced anxiety, reduced depressive-like behavior and decreased HPA function. Rats selected for high anxiety behavior exhibit increased HPA function related to a SNP in the vasopressin locus resulting in an overexpression of vasopressin. Antagonism of the V(1b) receptor decreases anxiety and depressive-like behaviors in rodents, as well as HPA responsivity to stress. Taken together, these data indicate that affective disorders may be related to excessive vasopressin function and consequently that a treatment with vasopressin receptor antagonists may be an effective treatment.