In the normal human body pancreatic β-cells spend most of the time in a READY mode rather than in an OFF mode. When in the READY mode, normal β-cells can be easily SWITCHED ON by a variety of apparently trivial stimuli. In the READY mode β-cells are highly excitable because of their high input resistance. A variety of small depolarizing currents mediated through a variety of cation channels triggered by a variety of chemical and physical stimuli can SWITCH ON the cells. Several polymodal ion channels belonging to the transient receptor potential (TRP) family may mediate the depolarizing currents necessary to shift the β-cells from the READY mode to the ON mode. Thanks to the TRP channels, we now know that the Ca(2+)-activated monovalent cation selective channel described by Sturgess et al. in 1986 (FEBS Lett 208:397-400) is TRPM4, and that the H(2)O(2)-activate non-selective cation channel described by Herson and Ashford, in 1997 (J Physiol 501:59-66) is TRPM2. Glucose metabolism generates heat which appears to be a second messenger sensed by the temperature-sensitive TRP channels like the TRPM2 channel. Global knock-out of TRPM5 channel impairs insulin secretion in mice. Other TRPs that may be involved in the regulation of β-cell function include TRPC1, TRPC4, TRPM3, TRPV2 and TRPV4. Future research needs to be intensified to study the molecular regulation of the TRP channels of islets, and to elucidate their roles in the regulation of human β-cell function, in the context of pathogenesis of human islet failure.