Based on the painful effects of exposure to capsaicin, TRPV1 (transient receptor potential vanilloid subfamily member 1) localization is most readily associated with peripheral sensory neurons, however, TRPV1 is now known to be expressed, albeit at lower levels, in the spinal cord, brain and a wide-range of non-neuronal cells. The latter includes epithelial cells (e.g. keratinocytes, urothelium, gastric epithelial cells, enterocytes, and pneumocytes) through vascular endothelium and cells of the immune system (e.g. T-cells and mast cells) to smooth muscle, fibroblasts and hepatocytes. Despite extensive research, the physiological function of TRPV1 in the brain and in non-neuronal tissues remains elusive. The preliminary results are exciting, but many are unconfirmed and/or contradictory. As yet, studies with TRPV1 knock-out mice have proven unhelpful in clarifying such biological roles. Now that a range of potent and selective TRPV1 antagonists are available in this rapidly expanding research field, further understanding of the biological roles of TRPV1 throughout the body is within reach. In this article, we will summarize the known roles of peripheral TRPV1 receptors in physiology and disease and review the current perspectives for the therapeutic potential of TRPV1 agonists and antagonists in the treatment of a wide range of conditions such as pain, cancer, migraine, chronic cough, asthma, rectal hypersensitivity, inflammatory bowel disease, obesity, overactive bladder and diabetes. New applications of targeting central TRPV1 receptors are reviewed in the accompanying article by Starowicz et al. (in this issue).