Recent cloning of a family of genes encoding inwardly rectifying K⁺ channels has provided the opportunity to explain some venerable problems in membrane biology. An expanding number of novel inwardly rectifying K⁺ channel clones has revealed multiple channel subfamilies that have specialized roles in cell function. The molecular determinants of inward rectification have been largely elucidated with the discovery of endogenous polyamines that act as voltage-dependent intracellular channel blockers, and with the identification of a critical site in the channel that mediates high-affinity block by both polyamines and Mg²⁺.