Exposure of circulating blood to collagen after vessel injury has been recognized as a primary event in arterial thrombosis for many years but an understanding of the molecular basis of this response has only recently materialized. Platelet collagen interactions are initiated indirectly by interaction of platelet glycoprotein Ib (GPIb) with collagen-bound von Willebrand Factor (vWF). Slowed, rolling platelets firmly adhere following the generation of platelet activating signals in a process initiated by the platelet collagen receptor glycoprotein VI (GPVI). The contribution of the first platelet collagen receptor identified, integrin α2β1, remains controversial. α2β1 is not required for platelet responses to collagen under many experimental conditions but GPVI and other intracellular signals may activate the integrin, which is likely to play a later, secondary role. In vivo studies of arterial thrombosis using genetically modified mice suggest that blockade of plateletcollagen interactions may be a highly effective means of inhibiting arterial thrombosis. Recent studies have generated a more complete model of the molecular basis of plateletcollagen responses and provided both the means and incentive to create novel therapeutic agents aimed at blocking this process to treat human atherothrombotic diseases such as myocardial infarction and stroke.