In responding to cytoplasmic nucleotide levels, ATP-sensitive potassium (K_ATP) channel activity provides a unique link between cellular energetics and electrical excitability. Over the past ten years, a steady drumbeat of crystallographic and electrophysiological studies has led to detailed structural and kinetic models that define the molecular basis of channel activity. In parallel, the uncovering of disease-causing mutations of K_ATP has led to an explanation of the molecular basis of disease and, in turn, to a better understanding of the structural basis of channel function.