Extracellular ATP is a critical signaling molecule that is found in a wide range of concentrations across cellular environments. The family of nonselective cation channels that recognize extracellular ATP, termed P2X receptors (P2XRs), is composed of seven sub-types (P2X1-P2X7) that assemble as functional homo-trimeric and hetero-trimeric ion channels. The therapeutic potential of P2XRs is an emerging area of research, as overactive P2XRs have been shown to play pathophysiological roles in neuro-inflammation, vascular inflammation, and cell division. Although there are currently no FDA-approved drugs targeting P2XRs, structure-based drug design can provide unique and insightful details into the intricacies of each receptor to facilitate sub-type selective ligands. Here, we highlight potential therapeutically targetable sites in the P2XR family and how single-particle cryogenic electron microscopy (cryo-EM) can be used to advance drug discovery, focusing on two cryo-EM structures; the endogenous agonist ATP bound to P2X7 and the noncompetitive antagonist JNJ-47965567 bound to P2X7.