IN BRIEF This article reviews studies related to biological mechanisms that make weight loss maintenance difficult. Approximately 50% of weight variance is reported to be determined by genetics and 50% by the environment (energy-dense foods and reduced physical activity). Body weight is tightly regulated by hormonal, metabolic, and neural factors. Hormonal adaptations (decreases in leptin, peptide YY, cholecystokinin, and insulin and increases in ghrelin, glucagon-like peptide 1, gastric inhibitory polypeptide, and pancreatic polypeptide) encourage weight gain after diet-induced weight loss and continue for at least 1 year after initial weight reduction. Weight loss also results in adaptive thermogenesis (decreased resting metabolic rate), which is also maintained long-term. Neural factors such as dopamine also signal the need to respond to an increased desire for fatty foods after weight loss.