Obesity is today one of the commonest of life-threatening diseases in developed countries and generally results from an imbalance between energy intake and energy expenditure. Although there is increasing evidence for a genetic basis of obesity in some clinical syndromes, this seems to be the cause only in a limited number of patients and obesity is far from being considered as a gene-related disease. Eating is a complex and multifactorial process involving autonomous pathways that transfer sensory and motor information between the entire length of the digestive tract and the central nervous system. Modulation of the amount of energy that we take in as food involves several mechanisms and networks that connect the brain with the gut, this process being key to the regulation of body weight over time, as well as to the modification of long-term eating behaviors. Furthermore, this axis is closely coupled to other systems that are involved in energy homeostasis, namely, food preference, energy expenditure, and lifestyle. The identification of several neuropeptides that modulate eating behavior in various ways, along with studies performed in animal models, have focused attention on the role of these molecules and their clinical implications in the development of obesity in humans.