Capsaicin (CAP) is the chief active ingredient of natural chili peppers. It has culinary and medicinal benefits. CAP activates its receptor, transient receptor potential vanilloid subfamily 1 (TRPV1), which is expressed in the sensory and motor neurons, adipocytes, liver, vascular smooth muscle cells, neuromuscular junction, skeletal muscle, heart and brain. The specificity of CAP to activate TRPV1 is the fundamental mechanism for its medicinal benefits to treat pain, obesity, hypertension, and other diseases. Preclinical data from rodent model of high fat diet-induced obesity collectively suggest that CAP exerts its effects by activating TRPV1 signaling pathway, which stimulates thermogenic mechanisms in the white and brown adipose tissues to induce browning of white adipose tissues and brown adipose tissue thermogenesis. This leads to enhancement of metabolic activity and thermogenesis to counter obesity. Although CAP and its pungent and nonpungent analogs are used in human clinical studies, their effects on satiety and energy expenditure have been the highlights of such studies. The precise mechanism of action of CAP has not been evaluated in humans. This article summarizes these data and suggests that long-term safety and tolerance studies are important for advancing CAP to treat human obesity.