The superior efficacy of bariatric surgery compared with intensive medical treatment in reversing metabolic disease is now well accepted, but the critical mechanisms remain unknown. Unlike dieting, which triggers strong counter-regulatory responses such as hunger and craving, some obesity surgeries appear to permanently reset the level of defended body weight. Understanding the molecular mechanisms behind successful surgery would thus go a long way in developing future ‘knifeless' treatment options. Major candidates include changes in gut–brain signaling by hormones, bile acids, and other still unidentified factors. By re-sensitizing homeostatic regulatory circuits in the hypothalamus and hedonic-motivational processing in corticolimbic systems to internal signals, bariatric surgery could thus lead to a state of being content with less.