Over the past four decades, a variety of interventions have been used for the treatment of clinical depression and other affective disorders. Several distinct pharmacological compounds show therapeutic efficacy. There are three major classes of antidepressant drugs: monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and tricyclic compounds. There are also a variety of atypical antidepressant drugs, which defy ready classification. Finally, there is electroconvulsive therapy, ECT. All require chronic (2-3 weeks) treatment to achieve a clinical response. To date, no truly inclusive hypothesis concerning a mechanism of action for these diverse therapies has been formed. This review is intended to give an overview of research concerning G protein signaling and the molecular basis of antidepressant action. In it, the authors attempt to discuss progress that has been made in this arena as well as the possibility that some point (or points) along a G protein signaling cascade represent a molecular target for antidepressant therapy that might lead toward a unifying hypothesis for depression. This review is not designed to address the clinical studies. Furthermore, as it is a relatively short paper, citations to the literature are necessarily selective. The authors apologize in advance to authors whose work we have failed to cite.