The sulfonylurea receptors (SURs) ABCC8/SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K⁺ selective pores, either K_IR6.1/KCNJ8 or K_IR6.2/KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K⁺ channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K⁺ (K_ATP) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotide-binding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic β cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K_ATP channel activity by a K_IR6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K_ATP channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues.