Since their discovery over 20 years ago, it has been recognized that adenosine triphosphate-sensitive potassium (K_ATP) channels play a critical role in insulin secretion. When these channels are open, insulin secretion is inhibited, and when they are shut, secretion is initiated. Consequently drugs, mutations, or changes in beta-cell metabolism that open K_ATP channels decrease insulin secretion and may cause diabetes, whereas those manipulations that close K_ATP channels have the opposite effect, increasing insulin secretion and hypoglycemia. This chapter reviews our current knowledge of the pancreatic beta-cell K_ATP channel, and discusses new data on its structure, structure-function relationships, and role in disease.