A multidisciplinary effort over twenty years has provided deep insight into the nature of K(ATP) channels. First discovered in cardiomyocytes and pancreatic beta-cells, as ubiquitous sensors of the ADP/ATP ratio they are implicated in multiple disorders characterized by the uncoupling of excitation from metabolism. Composed of two disparate subunits these large octameric channels present a formidable challenge to scientists interested in understanding mechanism in physical, chemical, and structural terms. Post-cloning studies have defined the domains and interactions, within and between the nucleotide-inhibited K(IR) pore and nucleotide-stimulated, drug-binding core of the ATP-Binding Cassette (ABC) regulatory subunits, that control channel assembly and gating. Determination of the three-dimensional structures of the bacterial prototypes of the channel subunits allowed homology modeling and has provided increasingly detailed mechanistic understanding. Here I review the early electrophysiology and molecular biology of K(ATP) channels, cover biophysical principles governing their single channel kinetics, integrate this with current efforts to understand ligand-recognition and gating within the pore and SUR core, and propose a mechanism of coupling based on recent identification of a SUR gatekeeper module and first composite models of (SUR/K(IR) 6.0)(4) complexes. This mechanism, based on interactions between inter-K(IR) subunit ATP-binding pockets and a unique bi-directional regulatory apparatus comprised of elements from the gatekeeper and K(IR) amino terminus, provides a molecular perspective for understanding the biophysical basis underlying the polar effects of pathogenic mutations in K(ATP) channel subunits.