After decades of effort, the field of depression research is far from understanding how antidepressant drugs mediate their clinical effects. The time lag of 2-6 weeks of therapy that is necessary to obtain antidepressant efficacy indicates a requirement for long-term regulation of molecules activated by drug treatment. The focus of antidepressant research has thus expanded from examining acute monoamine-mediated mechanisms to include long-term transcriptional regulators such as cAMP response element-binding protein (CREB) and trophic factors such as brain-derived nerve growth factor and insulin-like growth factor. In addition, the recent discovery of antidepressant-induced neurogenesis provides another avenue by which antidepressants might exert their effects. Current efforts are aimed at understanding how CREB and trophic factor signaling pathways are coupled to neurogenic effects and how alterations in behavioral, molecular and cellular endpoints are related to the alleviation of the symptoms of depression.