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Extensive human and animal model data show that nutrition and other environmental influences during critical periods of embryonic, fetal, and early postnatal life can affect the development of body weight regulatory pathways, with permanent consequences for risk of obesity. Epigenetic processes are widely viewed as a leading mechanism to explain the lifelong persistence of such "developmental programming" of energy balance. Despite meaningful progress in recent years, however, significant research obstacles impede our ability to test this hypothesis. Accordingly, this review attempts to summarize progress toward answering the following outstanding questions: Is epigenetic dysregulation a major cause of human obesity? In what cells/tissues is epigenetic regulation most important for energy balance? Does developmental programming of human body weight regulation occur via epigenetic mechanisms? Do epigenetic mechanisms have a greater impact on food intake or energy expenditure? Does epigenetic inheritance contribute to transgenerational patterns of obesity? In each case, significant obstacles and suggested approaches to surmounting them are elaborated.