Mood disorders, including major depression and bipolar disorder, remain a major unmet medical need as current antidepressant and mood stabilizing therapies require chronic treatment for efficacy and are not effective in all patients. Multiple deficits, including cell atrophy and loss, have been observed in limbic and cortical brain regions of patients with mood disorders and in stressed animals. It is thought that antidepressant and mood stabilizing medications restore these deficits by reestablishing proper patterns of gene expression and function. In support of this hypothesis, numerous changes in gene expression and activity have been observed in limbic and cortical brain regions of mood disorder patients, and thymoleptic therapies have been shown to reciprocally regulate many of these changes. These findings have implicated four main signaling pathways in the pathophysiology and/or treatment of mood disorders, namely the cyclic-AMP, phosphoinositol, mitogen-activated protein kinase, and glycogen synthase kinase signaling cascades. Below we review this literature, and discuss potential targets for novel antidepressant and mood stabilizing drug design that are highlighted by these findings.