The central serotonin (5-hydroxytryptamine, 5-HT) system is an established modulator of ingestive behaviour. Pharmacological and genetic research implicates the serotonin 2C receptor (5-HT2CR) specifically in these effects. New selective 5-HT2CR agonists are currently being pursued for the treatment of human obesity. We sought to clarify how serotonin in general and the 5-HT2CR in particular modulate ingestive behaviour. The hypothalamus is a key brain region coordinating endocrine, autonomic, and behavioral responses to changes in energy availability. Through a combination of functional neuroanatomy, feeding, and electrophysiology studies in rodents, we report that 5-HT2CR agonists require functional melanocortin pathways to exert their effects on food intake. Specifically, we observed that anorectic serotonin drugs activate proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. We provide evidence that the 5-HT2CR is expressed on POMC neurons and contributes to this effect. Finally, we report that serotonin drug-induced hypophagia is attenuated by genetic inactivation of downstream melanocortin 4, but not melanocortin 3 receptors. A model is presented in which activation of the melanocortin system is downstream of serotonin and is necessary to produce the complete anorectic effect of serotonergic compounds and 5-HT2CR agonists.