The evolution of platelet directed pharmacotherapy in the prevention and treatment of patients with thrombotic disorders is based soundly on a rapidly expanding knowledge of platelet biology. Traditionally viewed, throughout most of its relatively brief history in medicine, as an anucleate, passive contributor to hemostasis, a more contemporary perspective acknowledges platelets as complex, multidimensional cells that participate actively in coagulation, vascular repair, angiogenesis and thrombosis within the micro and the macro-circulatory systems. Herein, we consider platelet-directed pharmacotherapy from these fundamental, biology-based exemplars--megakaryocytes, signal transduction and the platelet--coagulation protease interface. We also highlight the emerging biopharmacology platform of oligonucleotide platelet adhesion antagonists and their complementary antidotes.