The prototypical member of the vanilloid-responsive-like subfamily of transient receptor potential (TRP) channels is TRPV1. TRPV1 mediates aspects of nociception and neurogenic inflammation; however, new roles are emerging in sensation of both lumenal stretch and systemic tonicity. Although at least six non-synonymous polymorphisms in the human TRPV1 gene have been identified, there has been no systematic investigation into their functional consequences. When heterologously expressed in HEK293 cells, all variants exhibited equivalent EC₅₀ for the classical agonist, capsaicin. This agonist elicited a greater maximal response in TRPV1^I315M and TRPV1^P91S variants (relative to TRPV1^WT), as did a second agonist, anandamide. Expression of these two variants in whole-cell lysates and at the cell surface was markedly greater than that of wild-type TRPV1, whereas expression at the mRNA level was either unchanged (TRPV1^P91S) or only very modestly increased (TRPV1^I315M). Incorporation of multiple non-synonymous SNPs, informed by the population-specific haplotype block structure of the TRPV1 gene, did not lead to variant channels with unique features vis-a-vis capsaicin responsiveness. Recently, polymorphisms/mutations were identified in two highly conserved TRPV1 residues in the non-obese diabetic (NOD) murine model. Incorporation of these changes into human TRPV1 gave rise to a channel with a normal EC₅₀ for capsaicin, but with a markedly elevated Hill slope such that the variant channel was hyporesponsive to capsaicin at low (< 10 nM) and hyper-responsive at high (> 10 nM) doses. In aggregate, these data underscore expression-level and functional differences among naturally occurring TRPV1 variants; the implications with respect to human physiology are considered.