Human obesity represents a major threat to global well-being, and a better understanding of its pathogenic mechanisms may lead to the development of effective therapeutic strategies. In this article, we will review the existing literature dealing with the role of serotonin in the pathogenesis of obesity. Using a number of models, we demonstrate that abnormal hypothalamic serotonergic neurotransmission and / or deranged receptor expression / sensitivity exists, and that these are closely associated with changes in the concentrations of dopamine, another hypothalamic monoamine closely involved in the regulation of food intake. However, it is still difficult to ascertain whether these abnormalities are acquired in response to chronic overingestion resulting in obesity, which then drives further increases in food intake to preserve the status quo, or whether these are due to primary factors. The pivotal role of central serotonin in obesity is also strengthened by the evidence that the drugs licensed to interfere with food intake in obese patients involve the serotonergic system. But since their use, including sibutramine, may lead to potentially severe side effects, alternative strategy to increase hypothalamic serotonergic activity is also proposed.