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P2X receptors are membrane non-selective cation channels that gated in the presence of extracellular adenosine triphosphate (ATP) and related diand tri-phosphate nucleotides, that more commonly known for providing cells with energy. Binding of ATP to the excellular pocket of P2X triggers the opening of transmembrane pore, which allows sodium, magnesium, potassium, calcium and other organic ions to flow down their electrochemical gradients. Because seven P2X receptor subtypes (P2X1-7) are widely distributed in excitable and nonexcitable cells of vertebrates, P2X receptors mediate many physiology processes including synaptic transmission and thrombocyte aggregation. These ion channels are also involved in the pathology of several disease states, playing key roles in inter alia afferent signaling (including neuropathic pain), regulation of renal blood flow, vascular endothelium, and chronic inflammation, and thus are potential targets for drug development. The recent discovery of potent and highly selective antagonists for P2X receptors, through the use of high-throughput screening, have helped to further understand the P2X receptors pharmacology and provided new evidence that P2X receptors play specific roles, such as in chronic pain states. In this review, we place previous work of P2X in the context of three-dimensional (3D) crystal structure of Zebrafish P2X4.1 (ΔzfP2X4.1), discuss how the P2X family of ion channels have distinguished themselves as potential new drug targets, and try to differentiate between drugs which are useful research tools, helpful in understanding the physiological roles of these receptors. We also summarize the key questions and challenges, which await researchers’ further work as we move forward to the new drug development era of P2X receptors. We are optimistic that safe and effective candidate drugs will be suitable for progression into clinical development.