Secretion is a critical platelet function, essential in both physiological and pathophysiological activities of platelets. Granules constitute more than 10% of total platelet volume and account for nearly a third of total platelet membrane. The classic platelet granule types include dense granules, α-granules, and lysosomes. Dense granules contain high concentrations of bioactive amines, cations, polyphosphates, and nucleotides. α-Granules contain hundreds of different proteins, including coagulation factors, growth factors, proteases, and transmembrane receptors. Lysosomes represent a minor granule population that contain enzymes involved in the degradation of proteins, carbohydrates, and lipids. More recently, the dense tubular system has been established as a non-canonical platelet secretory system. With this diversity of contents, platelet exocytotic pathways participate in many functions, including hemostasis and thrombosis, inflammation, atherosclerosis, antimicrobial host defense, malignancy, angiogenesis, and wound healing. The secretion of platelet contents is tightly controlled so as to permit rapid release of cargo in response to injury while preventing inadvertent release of potentially deleterious contents. This chapter will review established and recent studies describing platelet granule content and function, the mechanisms of granule secretion from platelets, and human platelet granule deficiency syndromes.