Temperature-sensitive transient receptor potential (TRP) channels are structurally similar to other tetrameric cation channels, but can be potently activated by heat. Recent studies suggest that the pore-forming region directly participates in activation gating. In this chapter, we summarize major findings from both structural and functional studies concerning the gating role of the pore region, focusing in particular on TRPV1. The emerging picture is that the peripheral S1-S4 region of TRPV1 is rigid and plays a supporting role for thepore to undergo conformational rearrangements. This places the pore region in the center of activation gating.