The obesity epidemic demands more insight into genetic predisposition, mechanisms, prevention and therapeutic interventions. Opinions about how to prioritize obesity research in the next decade are many and highly varied. However, in this article I have chosen three areas of focus that arguably should be at the top of the list. These include: (1) the physiologic basis of body weight and body fat regulation; (2) epigenetic mechanisms of energy balance; and (3) the prevention of obesity. The approach needs to be translational and bi-directional with a strong emphasis on basic science including studies of relevant gene expression and animal models of energy balance. Clinical research into mechanisms can challenge the existing paradigms that could direct research back to more basic understanding or to applications to populations at risk. Communication between scientists and physicians at the far end of the spectrum needs new and ongoing emphasis.