The influence of serotonin (5-HT) on neuronal function is mediated by regulation of receptor-coupled intracellular signal transduction pathways, and the therapeutic action of 5-HT selective reuptake inhibitors (SSRIs), as well as other types of antidepressants, most likely involves regulation of these intracellular pathways. The cyclic adenosine monophosphate (cAMP) second messenger system is one pathway that could be involved in antidepressant action. Chronic administration of antidepressants, including SSRIs, up-regulates the cAMP pathway at several levels, including increased expression of the cAMP response element binding protein (CREB). Among the multiple target genes that could be regulated by CREB and that could be involved in antidepressant actions and the pathophysiology of depression in brain-derived neurotrophic factor (BDNF). Stress decreases the expression of BDNF, and reduce levels of this neurotrophic factor could contribute to the atrophy and decreased function of stress-vulnerable hippocampal neurons. In contrast, antidepressant treatment increases the expression of BDNF in hippocampus, and could thereby reverse the stress-induced atrophy of neurons or protect these neurons from further damage. Up-regulation of the cAMP and BDNF systems has resulted in a novel model for the mechanism of action of antidepressants and new targets for the development of therapeutic agents.