The management of chronic, neuropathic pain with drugs other than narcotic agents is problematic. The cloning of TRPV1 (vanilloid receptor) and the recognition of endovanilloid signaling via TRPV1 in pain and inflammatory hyperalgesia have identified a new target for drug development and launched a massive effort on part of the pharmaceutical industry to discover novel TRPV1 antagonists. It is hoped that such antagonists may function as potent analgesic agents by blocking the combined action of heat, protons, and endovanilloids on TRPV1 either by preventing endovanilloid binding or by some direct inhibitory action on TRPV1. The recognition of TRPV1 overexpression during inflammatory hyperalgesia, diabetic neuropathy, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS) has lent further support to this concept. The last two observations are particularly exciting in that the management of patients with IBD or IBS with existing drugs may be frustrating. Locally active TRPV1 antagonists may provide a relief for such patients with few, if any, potential adverse effect. With regard to orally active TRPV1 antagonists, new findings raise concerns about unforeseen side effects (e.g., gastric ulcer formation, hypertension, central nervous system (CNS) effects). As yet, it is unclear if these findings obtained in experimental animals also hold true in patients. If they do, it remains to be seen whether the beneficial actions of TRPV1 antagonists outweigh their adverse effects.