Worldwide prevalence reports for obesity and diabetes over recent decades suggest that the chronic management of metabolic disease will dominate health care for the foreseeable future. Feeding behaviors contributing to obesity have been recognized for nearly a half-century, many of the key molecular mediators of central nervous system appetite control have been identified, and novel pharmacological agents have been introduced to treat obesity. However, less than robust results from medical management have promoted the pursuit of alternative clinical and scientific approaches. Anatomical interventions including bariatric surgery are gaining acceptance despite uncertainties about patient selection and long-term consequences. In rodents, manipulating the microbial community structures that constitute the intestinal microbiota can impact body composition, but how this information may translate to humans is still unclear. The realization that brown-like adipose tissue exists in humans has prompted provocative studies in animals demonstrating that adipose depots can be induced to carry out inefficient metabolism, a process that if translated to humans could alter energy balance to treat obesity and diabetes. A common obesity complication is type 2 diabetes, but obesity does not universally lead to diabetes, providing some support for the notion of “healthy” obesity. For those with obesity-associated diabetes, recent therapeutic options appear to decrease certain diabetes complications although the responsible mechanisms are poorly understood. Emerging evidence suggests that a combination of genetic and metabolic profiling could help guide management, but such an approach will also require behavioral and population-based strategies to address the failure of many providers and patients to utilize proven therapies.