Laboratory studies support a role of capsaicin as an anti-obesity agent. Intestinal mucosal afferent nerves appear to play a role in controlling adipose tissue distribution between visceral and subcutaneous sites. Activation of the transient receptor potential vanilloid-1 channels by capsaicin prevents adipogenesis. A neurogenic mechanism modulates the regulation of fat metabolism by transient receptor potential vanilloid-1-sensitive sensory nerves. A neural pathway enables the selective activation of the central network that regulates brown adipose tissue sympathetic nerve activity in response to a specific stimulation of gastrointestinal transient receptor potential channels. Dietary capsaicin reduces metabolic dysregulation in obese/diabetic mice by enhancing expression of adiponectin and its receptor. The effects of capsaicin in adipose tissue and liver are related to its dual action on peroxisome proliferator-activated receptor alpha and transient receptor potential vanilloid-1 expression/activation. Local desensitization of the abdominal capsaicin-sensitive fibers attenuates the hypometabolic adaptation to food deprivation. Truncal vagotomy leads to significant reductions in both diet-induced weight gain and visceral abdominal fat deposition. Vagal de-afferentation leads to a more modest, but clinically and statistically significant, reduction in visceral abdominal fat. Thermogenesis and lipid metabolism-related proteins are altered upon capsaicin treatment in white adipose tissue. Capsaicin induces apoptosis and inhibits adipogenesis in preadipocytes and adipocytes. Epidemiologic data show that consumption of foods containing capsaicin is associated with a lower prevalence of obesity. Clinical evidence supports a role of capsaicin as an anti-obesity agent. Both oral and gastrointestinal exposure to capsaicin increase satiety and reduce energy and fat intake; the stronger reduction with oral exposure suggests a sensory effect of capsaicin. Bioactive components containing capsaicin may support weight maintenance after a hypocaloric diet. Capsaicin consumption 1 h before low intensity exercise is a valuable supplement for the treatment of individuals with hyperlipidemia and/or obesity because it improves lipolysis. Capsinoid ingestion increases energy expenditure through the activation of brown adipose tissue in humans. Capsinoid ingestion is associated with an increase in fat oxidation that is nearly significant; and two common genetic variants may be predictors of response. Further clinical research to develop convenient approaches for obese individuals to take advantage of this common dietary ingredient to prevent the onset or curtail the progression of obesity will be instructive and clinically relevant.