5-hydroxytryptamine (5-HT, serotonin) is a major neurotransmitter involved in the modulation of behavior, the manifestation of various psychiatric disorders, and is a pharmacological target in the treatment of depression and anxiety disorders. The physiological effects of serotonin are modulated by a variety of proteins that regulate its synthesis, storage, release, uptake and degradation. In addition, serotonin signaling is mediated by at least 14 distinct receptors. Alterations in the expression of genes that regulate the biological effects of serotonin in the brain could alter serotonergic signaling, and thus could ultimately alter behaviors where serotonin has been implicated. The purpose of this chapter is to describe the behavioral consequences of manipulation of genes that regulate serotonergic signaling in rodents and to review analogous genetic association studies in humans that relate to psychiatric disorders, with a particular focus on depression and anxiety disorders. Many of these studies provide supportive evidence of a role for the serotonergic system in various behavioral responses related to depression and anxiety, as well as other psychiatric disorders. In particular, dysfunction of tryptophan hydroxylase, the serotonin transporter (SERT) or 5-HT1A receptors can induce behaviors in rodents that are associated with anxiety and depression, and can also alter behavioral responses to antidepressant treatments. Moreover, many of these findings are supported by human genetic association studies. Studies in rodents also suggest that interference with SERT or 5-HT1A receptor function specifically during brain development can program anxiety levels and depression in adulthood. Finally, while some evidence suggests that other components of the serotonergic system might also play important roles in these disorders, such findings remain to be refined using genetically modified mice, selective pharmacological tools or human genetic association studies. © 2010, Elsevier Science & Technology. All rights reserved.