Excessive adiposity results from an imbalance in energy homeostasis, whereby the consequences of excessive food intake are not balanced by increased energy expenditure. The increasing prevalence of excessive adiposity now involves more than 1 billion individuals worldwide. Of these, one half is obese and susceptible to comorbidities such as insulin resistance, type 2 diabetes, hyperlipidemia, and hypertension, which accelerate atherosclerosis. Lifestyle changes that have resulted largely in decreased physical activity now require a greater understanding of energy use that may allow better strategies for obesity control, because traditional methods of decreasing food intake and/or increasing exercise have not been successful without considerable behavioral counseling. This review focuses on the cell biology of white and brown fat tissue as well as on the central obesity that explains the comorbidities of the metabolic syndrome. Recent advances regarding the roles of central and autonomic nervous system regulation involved in fat remodeling are discussed, including the hypothalamic regulation of food intake and intestinal modulation, which affects satiety and peripheral energy expenditure. Finally, the new knowledge of cellular transcription factor regulation of energy expenditure is explained, whereby genes regulate mitochondriogenesis within adipocytes, liver, and muscle for both coupled and uncoupled oxidative phosphorylation-induced energy and heat expenditure, respectively. Newly discovered agonists of these transcription factors may now be realized that enhance energy expenditure. Strategies that combine such pharmacotherapies with lifestyle changes including enhanced physical activity and proper dietary intake may then provide the deterrents to excessive adiposity and its comorbidities, which now threaten human longevity.