Under normal conditions, the homeostasis of energy intake is maintained in the hypothalamus by 1) transducing metabolic and sensorial inputs arising from the periphery into neuronal response, 2) integrating the information originating from different tissues, and 3) triggering the appropriate feeding responses. If cancer anorexia is considered a disruption of the physiologic mechanisms controlling energy intake, it is conceivable that its pathogenesis may lie in an abnormal input of information to the hypothalamus, its defective transduction and integration, or the induction of exaggerated and inappropriate feeding responses. Currently available data suggest that the pathogenesis of cancer anorexia is multifactorial and involves most of the neuronal signaling pathways modulating energy intake. Thus, a number of factors has been proposed as putative mediators of cancer anorexia, including hormones (e.g., leptin), neuropeptides (e.g., neuropeptide Y), cytokines (e.g., interleukin-1, interleukin-6, tumor necrosis factor), and neurotransmitters (e.g., serotonin and dopamine). However, it is unlikely that they represent separate and distinct pathogenic mechanisms; rather, it appears that close interrelationships may exist among them. In line with this reasoning, consistent experimental and human data suggest that hypothalamic monoaminergic neurotransmission and serotonergic activity in particular may represent a major target on which different anorexia-related factors converge. Thus, interfering pharmacologically with hypothalamic serotonin synthesis and activity has been tested as a therapeutic strategy in anorectic cancer patients with encouraging results. However, more clinical options will be available by revealing the complex interactions between the many factors participating in controlling energy intake under normal and pathologic conditions. Further, modulation of hypothalamic activity also might result in reduced catabolic signals to skeletal muscles, thus improving the cachexia associated with cancer.