Platelet membrane glycoprotein (GP) VI (GPVI) has been identified relatively recently as compared to other major platelet glycoproteins such as the GPIbVIX complex and integrin αIIbβ3. This is probably due to the limited clinical manifestations associated to GPVI deficiency, although strong evidence has been accumulated during the past 25 years that this receptor is critically involved in disease. GPVI is characterized by its potential to promote high levels of platelet activation, directly and also indirectly through its ability to efficiently stimulate amplification loops by soluble agonists such as adenosine diphosphate (ADP), thromboxane A2 (TXA2), and thrombin. GPVI initiates and amplifies thrombus growth and plays an important role in stabilizing the aggregate through continuous signaling. Consequently, GPVI plays a particularly important role in arterial thrombosis. In addition, a number of studies reveal that GPVI contributes to many processes beyond thrombosis, including inflammation, host defense, and cancer dissemination.