Over the past decade, the focus of research into the pathophysiology of mood disorders (bipolar disorder and unipolar depression in particular) has shifted from an interest in the biogenic amines to an emphasis on second messenger systems within cells. Second messenger systems rely on cell membrane receptors to relay information from the extracellular environment to the interior of the cell. Within the cell, this information is processed and altered, eventually to the point where gene and protein expression patterns are changed. There is a preponderance of evidence implicating second messenger systems and their primary contact with the extracellular environment, G proteins, in the pathophysiology of mood disorders. After an introduction to G proteins and second messenger pathways, this review focuses on the evidence implicating G proteins and two second messenger systems-the adenylate cyclase (cyclic adenosine monophosphate, cAMP) and phosphoinositide (protein kinase C, PKC) intracellular signaling cascades-in the pathophysiology and treatment of bipolar disorder and unipolar depression. Emerging evidence implicates changes in cellular resiliency, neuroplasticity and additional cellular pathways in the pathophysiology of mood disorders. The systems discussed within this review have been implicated in neuroplastic processes and in modulation of many other cellular pathways, making them likely candidates for mediators of these findings.