Serotonin modulates numerous processes in the central nervous system related to anxiety and fear, mood, aggression, sleep, ingestive behaviors, reward systems, and psychosis. Serotonergic dysfunction has been implicated in several neuropsychiatric conditions but efforts to develop more specific pharmacological agents have been hampered by the complexity of this system at the receptor level. There are at least 14 distinct receptors that mediate the effects of serotonin as well as several enzymes that control its synthesis and metabolism but very few pharmacological agents are able to selectively target a single receptor. Several groups including ours have used a genetic strategy to ablate specific serotonin receptors in an effort to dissect out their functions in the central nervous system. The strength of this approach is the high degree of specificity that can be achieved in the knockout (gene inactivation) approach since a single receptor gene can be selectively targeted. To date several inactivation mutations of specific serotonin receptors have been generated producing interesting behavioral phenotypes related to anxiety, depression, drug abuse, psychosis, and cognition. In many cases knockout mice have been able to confirm what has already been suspected based on pharmacological studies. In other instances, mutations have demonstrated new functions of serotonergic genes in development and behavior. In this review, the current literature regarding phenotypic changes in mice bearing inactivation mutations of serotonin receptors, the serotonin transporter, and the monoamine oxidase A will be discussed and major findings emphasized.