There is a significant gap between advances in medication for mental disorders and the present static situation of biological diagnosis and monitoring treatment. The system of neural transmission and signal transduction is a complicated, highly regulated cascade of biochemical events. Growing evidence suggests that receptor-G-protein coupling may be involved in both the pathogenesis and treatment of mood disorders. Our knowledge concerning the basic mechanisms underlying the phenomenon of desensitization, internalization, downregulation and resensitization of the G-protein-coupled receptor has been advanced during the last decade. The present review discusses the possible involvement of regulators of G-protein-coupled receptor-G-protein coupling: beta-arrestins, G-protein-coupled receptor kinases and phosducin-like proteins, as well as beta-arrestins alternative signaling events, in the pathophysiology, diagnosis and treatment monitoring of mood disorders and in the mechanism of action of antidepressant medications.