While various bariatric surgeries provide both the largest and most durable weight loss of any currently available therapy, there remain great uncertainties around the mechanisms that produce such weight loss. At least some surgical approaches also reduce obesity-related comorbidities including type 2 diabetes and hyperlipidemia. These weight and metabolic successes put a premium on understanding how these surgeries exert their effects. We have been using a variety of mouse models to test specific hypotheses about key molecular targets that mediate the benefits of bariatric surgery. Bariatric surgery produces changes in a number of brain-gut signaling systems that result in profound changes in food intake and food selection. In addition to typical gut hormones, bariatric surgery results in changes in bile acids and bile acid signaling that are crucial for many of the behavioral and metabolic effects of the surgery. These insights make it possible to devise new treatment strategies that take advantage of the potent effects of these procedures but are less invasive and more scalable to tackle the obesity and diabetes epidemics.