To maintain normal circulation in the blood vessel while being able to form a hemastatic plug quickly at sites of vascular injury, the adhesiveness of platelets is dynamically regulated. Platelets in normal circulation are in a resting, non-adherent state. When vascular injury occurs, platelets are activated by contact with exposed subendothelial components such as collagen and collagen-bound von Willebrand factor or by soluble agonists such as thrombin and ADP. The activated platelets adhere and spread onto the subendothelial matrix, and aggregate to form a primary thrombus. Regulation of the adhesiveness of the platelets is achieved at the level of the ligand binding function of a major platelet adhesion receptor, the platelet glycoprotein IIb-IIIa complex (GPIIb-IIIa), also named integrin αIIbβ3 (Phillips et al., 1991; Ginsberg et al., 1995). Regulation of GPIIb-IIIa is a two-way process (Phillips et al., 1991; Ginsberg et al., 1995): on the one hand, the extracellular ligand-binding function of GPIIb-IIIa can be activated by intracellular signals of the platelet (inside-out signals) in response to agonists such as ADP and thrombin. Activated GPIIb-IIIa binds an abundant plasma protein, fibrinogen that forms bridges between platelets and thus mediates aggregation. Activated GPIIb-IIIa also binds ligands such as von Willebrand factor, fibronectin and vitronectin, which can mediate adhesion of platelets to the subendothelial matrix. On the other hand, ligand interaction with GPIIb-IIIa may be activated by activation of a ligand, and ligand binding to GPIIb-IIIa may trigger outside-in signals that result in a series of intracellular biochemical events leading to platelet responses such as spreading, secretion, the second wave of aggregation and release of pro-coagulant membrane vesicles. Nurden and Caen (Nurden et al., 1974) first reported that a lack of GPIIb-IIIa is responsible for the dysfunction of platelets in a hereditary hemostatic disorder, Glanzmann’s thrombasthenia. Since then, many aspects of the structure and function of GPIIb-IIIa and its role in hemostasis have been investigated and understanding has improved. This led to the development and clinical use of GPIIb-IIIa inhibitors for preventing and treating thrombosis (Coller et al., 1995; Tcheng, 1996). Despite these achievements, mechanisms of GPIIb-IIIa regulation and signaling are still obscure. These will be the major focus of this chapter.