The purinergic P2X receptors are ligand-gated cation channels activated by ATP and assembled as homo- or heterotrimers from seven cloned subunits (P2X1-7). All subunits present a common topology, with intracellular N- and C- termini, two transmembrane domains and a large, glycosylated and disulphide-rich extracellular domain. P2X receptors are present in virtually all mammalian tissues and regulate a large variety of responses like macrophage activation, cell proliferation and death, fast transmission at central synapses, contraction of smooth muscle cells, platelet aggregation. The development of ligands that selectively activate or block specific P2X receptor subtypes represent a novel promising strategy to obtain pharmacological tools for the treatment of pain, cancer, inflammation, and neurological and cardiovascular diseases. The publication of crystal structures of zebra fish P2X4 in apo and ATP-bound form represents a critical step for the analysis of receptor structure, the interpretation of mutagenesis data, and the depiction of ligand binding and receptor activation mechanism. In addition, the availability ofATP-competitive ligands presenting selectivity for P2Xreceptor subtypes provides useful information for the design of new potent and selective ligands with possibly improved pharmacokinetic profile, aimed at obtaining new drugs. Molecular modeling studies were performed to develop the structural models of the human P2X receptors in apo and ATP-bound form. These models allowed to analyse the role of some non-conserved residues at ATP binding site entrance and to study their interaction with some non-specific or subtype selective ligands.