Subendothelial collagen exposed to platelets after rupture of atherosclerotic plaques is the main trigger of platelet activation und acute arterial thrombotic occlusion leading to myocardial infarction or ischemic stroke. An efficacious antiplatelet therapy is essential to prevent atherothrombotic events. However, increasing potency of antiplatelet treatment is associated with an increased risk of bleeding limiting the clinical benefit for the patient since current antiplatelet strategies concomitantly affect hemostasis. Therefore, an unmet clinical need remains to develop antiplatelet strategies that selectively inhibit atherothrombosis without interfering with control of bleeding. Platelet glycoprotein VI (GPVI) plays a crucial role in collagen-induced activation and aggregation of platelets. Since GPVI is platelet-specific and strongly involved in the pathogenesis of arterial thrombosis without great impact on normal hemostasis, GPVI moved into the focus of novel approaches of antithrombotic therapy strategies. This review summarizes ligands, properties, function and downstream signaling of GPVI and discusses the potential of GPVI as target for novel therapeutic strategies in thrombotic and inflammatory diseases on the basis of recent scientific findings and currently ongoing clinical phase I and phase II trials.Copyright © 2020. Published by Elsevier Inc.