Summary α-Granules are essential to normal platelet activity. These unusual secretory granules derive their cargo from both regulated secretory and endocytotic pathways in megakaryocytes. Rare, inheritable defects of α-granule formation in mice and man have enabled identification of proteins that mediate cargo trafficking and α-granule formation. In platelets, α-granules fuse with the plasma membrane upon activation, releasing their cargo and increasing platelet surface area. The mechanisms that control α-granule membrane fusion have begun to be elucidated at the molecular level. SNAREs and SNARE accessory proteins that control α-granule secretion have been identified. Proteomic studies demonstrate that hundreds of bioactive proteins are released from α-granules. This breadth of proteins implies a versatile functionality. While initially known primarily for their participation in thrombosis and hemostasis, the role of α-granules in inflammation, atherosclerosis, antimicrobial host defense, wound healing, angiogenesis, and malignancy has become increasingly appreciated as the function of platelets in the pathophysiology of these processes has been defined. This review will consider the formation, release, and physiologic roles of α-granules with special emphasis on work performed over the last decade.