Adenine nucleotides (ADP and ATP) have been recognized for many years to play crucial roles in the physiological process of primary hemostasis and in the development and extension of arterial thrombosis. It took approximately 40 years from the identification of ADP as a small molecule derived from red blood cells inducing platelet adhesion to glass, to the completion of the repertoire of its receptors on platelets and the identification of its importance in hemostasis and thrombosis. ADP and ATP act on platelets through three distinct P2 receptors: the P2Y1 and P2Y12 receptors, which are G protein-coupled ADP receptors, and the P2X1 receptor, a ligand-gated cation channel activated by ATP. Each of these receptors plays a specific role during platelet activation and aggregation, with relevance to hemostasis and thrombosis. Beyond hemostasis and thrombosis, there is increasing evidence for a strong contribution of these receptors to chronic and acute inflammation.