Natural products, particularly from plants, have been extremely important contributors to our understanding of human physiology and the search for new medicinal agents. The ability of capsaicin, the pungent chemical component of chili peppers, to evoke pain via activation of peripheral sensory neurons being a prominent example. The study of capsaicin has fuelled pioneering research regarding sensory physiology for more than a century and, more recently, enabled the cloning of the vanilloid receptor (VR1; Caterina et al 1997) that is now known as TRPV1 within the wider Transient Receptor Potential (TRP) ion channel superfamily (Clapham, 2003). TRPV1 is often termed a multimodal receptor since, in addition to activation by a range of exogenous and endogenous chemical agonists such as capsaicin and anandamide, it can respond to multiple divergent stimuli such as heat (>42°C), protons (acid, pH<6) and changes in membrane voltage. TRPV1 activity is also subject to regulation by a host of intracellular signaling cascades that may terminate in changes in receptor phosphorylation or phosphatidylinositol-4,5-bisphosphate-mediated inhibition, and are implicated in the response to algogenic agents, inflammatory mediators and injury (Gunthorpe & Chizh, 2009). Knowledge regarding the biological effects of capsaicin, the lack of thermal hyperalgesia exhibited by TRPV1 knockout mice in response to inflammatory insult, and the anti-hyperalgesic effects of TRPV1 antagonists in a range of preclinical pain models has led to broad interest in the development of selective TRPV1 antagonists for the treatment of pain. Indeed, a number of selective multimodal TRPV1 antagonists have now been extensively characterized in preclinical studies and have entered clinical development for pain and other indications (Gunthorpe & Chizh, 2009). In concert with numerous studies that have aided our understanding of peripheral, spinal and supraspinal sites where TRPV1 receptors contribute to signaling in the pain pathway, extensive recent research efforts have also uncovered new and unexpected physiological roles for TRPV1. This includes a contribution to the homeostatic control of core body temperature where tonic TRPV1 inhibition by antagonist exposure can cause hyperthermia (Gavva et al 2007). TRPV1-mediated hyperthermia appears to be an ‘on-target’ effect since it has been reported for a number of distinct TRPV1 antagonists in a range of species including rat, dog, monkey and human and is absent in TRPV1 knockout mice. It may, therefore, pose a significant hurdle for the further development of such novel analgesic agents. Given these findings, recent experimental work has been initiated to gain a detailed understanding of the mechanism of TRPV1-mediated hyperthermia with a view to either controlling, minimizing or circumventing this issue. Current perspectives for identifying novel TRPV1 therapeutics avoiding hyperthermia ‘by design’ by selective inhibition of specific modes of TRPV1 activation, as well as other strategies, will be presented.