Alternative splicing allows multiple mRNAs to be generated from a single gene, which in turn can be translated into a group of diverse proteins with different roles and structures. The outcome of alternative splicing leads to the co-existence of multiple splice variants of a gene at different concentrations in different tissues. The pore-forming subunit of the K_ATP channel (K_IR6.x) and the regulatory sulfonylurea receptor (SUR_x) subunits exist in a 4:4 stoichiometry to form hetero-octameric ATP-sensitive potassium channel (K_ATP) channels, which are widely distributed in various types of tissues at either the plasma membrane (cellK_ATP) or mitochondrial inner membrane (the mitochondrial form of K_ATP channel, mitoK_ATP). They perform important physiological functions in regulating insulin secretion in pancreatic β-cells, providing ischemic protection in heart and brain, and regulating vascular tone in smooth muscles. Two separate genes, the regulatory subunit protein I (SUR1) and the regulatory subunit protein II (SUR2) encode the high- and low-affinity SUR, respectively. This review summarizes the current studies on the function and distribution of the SUR isoforms and alternative splice variants, and to a lesser extent the K_IR6.x subunits. The different isoforms and splice variants allow for many K_ATP channel combinations, and therefore, increases the channel diversity and the possibility of complexity in function.