The prevalence of excess fat mass is currently at unprecedented levels, with approximately two-thirds of adults in the United States having overweight or obesity. The population health impact of excess adiposity is significant, as it is related to increased risk of diabetes, hypertension, coronary heart disease, and cancer. Weight gain is inevitably caused by consuming excess calories relative to energy expended, but the etiology of obesity is highly complex and includes genetic, physiological, environmental, and psychosocial factors that contribute independently and jointly to weight gain. Although only a small number of single genetic abnormalities have been discovered that are related to obesity, research on the epigenetics of obesity is investigating the influence of behavioral, environmental, metabolic, and endocrine factors on genetic expression. There is growing interest on the correlation between physiological and behavioral stress and the role they play in developing overweight or obesity. For instance, high stress levels have been linked to weight gain and appear to inhibit successful weight loss. The interactions between the brain and endocrine hormones may play a role in activating this stress response toward reward seeking and appetite regulation. In addition, weight gain is associated with several commonly used medications including diabetes oral agents and insulin, antidepressants, psychotropic drugs, steroid hormones, and contraceptives. Knowledge of the complex contributors to weight gain varies among patients and health-care professionals, and lack of this awareness will result in both continued population-based obesity and unsuccessful long-term weight loss.