There is a significant gap between advances in medication for mental disorders and the present static situation concerning diagnosis and monitoring treatments in these disorders. Although significant morbidity is associated with depression, failure to appropriately diagnose individuals remains the primary obstacle to the effective management of this disorder. Heterotrimeric G proteins are a crucial point of convergence in the transmission of signals from a variety of primary messengers and their membrane receptors to their intracellular effectors. The increasing interest in the clinical perspective of altered G protein function has yielded important findings concerning the involvement of G proteins in the pathophysiology of mood disorders and in the biochemical mechanisms underlying the treatment of these disorders: 1) Lithium inhibition of β-adrenergic and muscarinic receptor-coupled G protein function was suggested as a single molecular site for both its antimanic and antidepressant therapeutic effects. Other antibipolar treatments were found to exert similar effects on G protein function. 2) Increased G protein functional and immunoreactive measures were detected in peripheral blood elements of patients with mania and in postmortem cerebral cortices of bipolar patients. 3) Reduced measures of G proteins were found in large-scale studies of lymphocytes from patients with depression and of SAD patients during winter depression. 4) Alterations in function and in quantity of both G s and G i are significantly correlated with the severity of depressive symptomatology. 5) Normalization of G protein measures in mood-disordered patients occurred under lithium, antidepressants, and ECT, as well as light therapy. 6) No structural or regulatory abnormalities in the gene for the G s α subunit were found in patients with bipolar disorder. As a state-dependent marker, G protein measures might be potentially used as an aid in the biochemical diagnosis of mood disorders and for the biochemical monitoring of the response to a specific treatment. Drug Dev. Res. 50:316-323, 2000.