Capsaicin is a constituent of chili pepper, and induces the burning sensation on the tongue. The site of action for capsaicin has been discovered as transient receptor potential vanilloid receptor subtype 1 (TRPV1) that resides on the membranes of pain- and heat-sensing primary afferent nerves. The immunohistochemical study on the stomach revealed that nerve fibers expressing TRPV1 exist along gastric glands in the mucosa, around blood vessels in the submucosa, in the myenteric plexus, and in the smooth muscle layers. High numbers of TRPV1-immunoreactive axons were observed in the rectum and distal colon. Therefore, capsaicin stimulates TRPV1 not only on the tongue but also in the gut. In this review, the mechanism of gastrointestinal mucosal defense enhanced by capsaicin was summarized. TRPV1 plays a protective role in gastrointestinal mucosal defensive mechanism. Hypersensitivity of afferent fibers occurs during gastrointestinal inflammation. Abnormalities of primary afferent nerve fibers are strongly associated with the visceral hypersensitive state in inflammatory bowel disease (IBD). The alteration of TRPV1 channels in mucosa contributes to the visceral hypersensitivity in colitis model mice. TRPV1-expressing neurons in the gut are thought to be extrinsic sensory afferent neurons that operate to maintain gastrointestinal functions under physiological and inflammatory states.