ADP and ATP play a crucial role in hemostasis and thrombosis and their receptors are potential targets for antithrombotic drugs. The ATP-gated channel P2X1 and the two G protein-coupled P2Y1 and P2Y12 ADP receptors selectively contribute to platelet aggregation. Due to its central role in the formation and stabilization of a thrombus, the P2Y12 receptor is a well established target of antithrombotic drugs like clopidogrel which has proved efficacious in many clinical trials and experimental models of thrombosis. Competitive P2Y12 antagonists have also been shown to be effective in experimental thrombosis as well as in several clinical trials. Studies in P2Y1 and P2X1 knock-out mice and experimental thrombosis models using selective P2Y1 and P2X1 antagonists have shown that, depending on the conditions, these receptors could also be potential targets for new antithrombotic drugs. Since both P2X1 and P2Y1 receptor inhibition result in milder prolongation of the bleeding time as compared to P2Y12 inhibition, the idea is put forward that combination of P2 receptor antagonists could improve efficacy with diminished hemorrhagic risk. However, further studies are required to validate such a point of view.