Capsicum peppers-including chili peppers, paprika, and red peppers-are native to the Americas but used worldwide in spicy dishes. Capsaicin, the active ingredient of Capsicum peppers, is used topically to treat musculoskeletal pain, neuropathy, and other conditions. Capsaicin binds the transient receptor potential vanilloid 1 (TRPV1), releasing substance P and desensitizing nerves with long-term use. Capsicum peppers and capsaicin products (eg, medications, cosmetics, pepper sprays) can provoke an irritant contact dermatitis, causing erythema and cutaneous burning. Capsaicin-induced dermatitis can be relieved by washing the area with soap, detergents, or oily compounds. Ice water or high-potency topical steroids also can help. Capsaicin is available in creams, lotions, and patches. Synthetic TRPV1-agonist injectables based on capsaicin are in clinical trials for use in localized pain. Capsaicin is a neuropeptideactive compound found in Capsicum peppers with many promising applications; however, dermatologists should be aware of possible skin reactions to these plants and medications derived from them.