The fact that obesity is a chronic disorder has traditionally focused experimental attention on the long-term controls of energy balance. Searches for therapeutic targets tend to concentrate on central integrative mechanisms and to largely ignore the visceral afferents and other peripheral mechanisms providing short-term controls of energy balance. Investigations of central mechanisms have yet to yield, however, any practical and effective treatments for correcting obesity. In this review, we survey some of the arguments for considering peripheral visceral afferent mechanisms as promising targets for future research on obesity. These arguments include (1) the observation that visceral afferents have the specializations, complexities, heterogeneities, and extensive distributions at key sites to provide exhaustive and dynamic feedback to control energy handling, (2) the fact that the most effective treatments yet developed for achieving long-term or permanent weight loss, namely gastroplasty and similar bariatric surgical procedures, clearly alter visceral afferent feedback from the gastrointestinal tract, and (3) experimental observations that suggest loss of visceral negative feedback can lead to overeating, positive energy balance, and obesity. Furthermore, even though excess adiposity is a disturbance in long-term energy regulation, it is instructive that obesity in the final analysis is developed, is maintained, and ultimately needs to be treated one meal at a time. When these considerations are taken in conjunction with concerns about side effects and risks that can be expected to accompany pharmacological therapies directed at central nervous system circuits, it would seem prudent to assess ways in which the feedback of visceral afferents might be enhanced or manipulated to support or synergize with other therapeutic strategies used in the management of excess energy intake.