Seminal discoveries in the bariatric surgery field have revealed a remarkable link between gastrointestinal physiology and obesity, a link that extends to remission of many metabolic diseases including type 2 diabetes and to risk of cardiovascular disease. Much of the beneficial health effects of bariatric surgery can be ascribed to weight loss. However, in the case of type 2 diabetes, resolution is so acute that it appears to be independent of the weight loss. These observations have created the intriguing scenario whereby altering gastrointestinal anatomy creates rapid physiological adaptations that manifest in normalization of glucose homeostasis. The cellular and molecular mechanisms that produce these favorable health changes are an area of intense scientific investigation. One leading hypothesis suggests that rerouting nutrient flow to the gut alters enteroendocrine signals and bile acid secretion that favors appetite suppression; increased energy expenditure and insulin action; and decreased inflammation, blood lipids, and hypertension. In addition, the gut microbiome has emerged as an area of particular interest with a focus on bacteria and metabolites that interact to influence weight regulation and metabolic health. The collective evidence presented herein provides strong support for an essential role for the gastrointestinal tract as a modulator of obesity-related disease. The gut is now considered a novel endocrine organ and a therapeutic target for prevention and treatment strategies that will benefit human health.