In the nervous system, ATP is co-stored in vesicles with classical transmitters and released in a regulated manner. ATP from the intracellular compartment can also exit the cell through hemichannels and following shear stress or membrane damage. In the past 30 years, the action of ATP as an extracellular transmitter at cell-surface receptors has evolved from somewhat of a novelty that was treated with skepticism to purinergic transmission being accepted as having widespread important functional roles mediated by ATP-gated ionotropic P2X receptors (P2XRs). This review focuses on work published in the last five years and provides an overview of (a) structural studies, (b) the molecular basis of channel properties and regulation of P2XRs, and (c) the physiological and pathophysiological roles of ATP acting at defined P2XR subtypes.