Following vascular injury, the adenosine nucleotide ATP is released from the dense granules of adhering and activated platelets, as well as from injured endothelial cells and damaged red blood cells. ATP instantaneously interacts with the ion channel P2X(1) in the platelet membrane, through autocrine and paracrine mechanisms, amplifying the initial phase of a platelet activation event. A multitude of platelet activation studies in vitro and in vivo have identified P2X(1) as a receptor with a distinct pharmacological profile, capable of regulating various intracellular signaling cascades, implicated in platelet function. This review discusses findings on the function of the platelet P2X(1) receptor and its downstream signaling pathways, collected over the last two decades, against more recent in vivo observations in thrombosis models in P2X(1) gene-deficient and transgenic mice. Our present understanding of its physiology has identified platelet P2X(1) as a target in the management of thrombosis, its inhibition potentially capable of platelet function modulation. In view of the availability of specific agonists and antagonists, P2X(1) is also discussed as a therapeutic target for antithrombotic therapy.