Obesity is the result of a mismatch between the amount of calories consumed and the amount of calories expended during an extended period of time. This relationship is described by the energy balance equation, which states the rate of change in energy storage depots in the body are equal to the rate of energy intake minus the rate of energy expenditure. Although this relationship may appear easy to understand based on simple mathematics, in reality, a variety of known and unknown systems influence the components of energy balance (energy storage, energy intake, energy expenditure). Clearly, if a complete understanding of energy balance was apparent, worldwide levels of obesity would not have reached pandemic proportions due to effective prevention and treatment strategies. The aim of the present article is to provide a brief overview of the components of energy balance and to identify 10 key topics and unanswered questions that would move the research field forward if addressed. These topics are intentionally diverse and range from general themes (e.g., methodological issues) to specific areas (e.g., intensity of exercise required to alter energy intake). Although this list is not meant to be exhaustive, it does provide a research agenda for scientists involved in the study of energy balance and recommendations for public health professionals developing obesity interventions.