Platelet granule secretion or exocytosis is required for normal platelet function and plays an important role in the pathogenesis of cardiovascular diseases. Platelets secrete molecules that amplify thrombosis, induce vascular remodeling, recruit and activate cells. The platelet secretory process begins in megakaryocytes where molecules are targeted to developing granules through specific vesicle trafficking and transporter mechanisms. Secretory granules may continue to mature in the circulation after the platelet has been released from the megakaryocyte. The platelet secretory process culminates when ligands interact with specific platelet receptors to trigger exocytosis. A convergence of new insights from several different organisms has begun to illuminate the molecular mechanisms responsible for the platelet secretory process, from granule development through membrane fusion and exocytosis.