TRPV1 is a noxious heat, capsaicin (vanilloid) and acid receptor for which the development of antagonists represents a novel therapeutic approach for the treatment of pain. TRPV1 antagonists have entered early clinical development and initial reports indicate that they have demonstrated pharmacodynamic effects consistent with TRPV1 antagonist activity and anti-hyperalgesic action in humans. Should these effects extend to the relief of symptoms experienced by patients with chronic pain then this class of compounds may offer one of the first novel mechanisms of action for the treatment for pain for many years. In this article we will discuss recent progress and challenges in the field in this highly competitive area of drug discovery.