ATP-sensitive potassium channels, termed KATP channels, link the electrical activity of cell membranes to cellular metabolism. These channels are heteromultimers of sulfonylurea receptor (SUR) and KIR6.X subunits associated with a 1:1 stoichiometry as a tetramer (SUR/KIR6.X forms the pores, whereas SUR regulates their activity. Changes in [ATP]i and [ADP]i gate the channel. The diversity of KATP channels results from the assembly of SUR and KIR6.X subtypes KIR6.1-based channels differ from KIR6.2 channels mainly by their smaller unitary conductance. SUR1- and SUR2-based channels are distinguished by their differential sensitivity to sulfonylureas, whereas SUR2A-based channels are distinguished from SUR2B channels by their differential sensitivity to diazoxide. Mutations that result in the loss of KATP channels in pancreatic beta-cells have been identified in SUR1 and KIR6.2. These mutations lead to familial hyperinsulinism. Understanding the mutations in SUR and KIR6.X is allowing insight into how these channels respond to nucleotides, sulfonylureas, and potassium channel openers, KCOs.