The pathogenesis of arterial thrombosis is complex and dynamic. Unlike venous thrombi, arterial thrombi typically form under conditions of high blood flow and are mainly composed of platelet aggregates, giving them the appearance of 'white clots'. Strong evidence suggests that arterial thrombi originate as a consequence of an injured atherosclerotic plaque, and that their formation involves the release of prothrombotic material (such as tissue factor), platelet aggregation, and platelet adhesion to the vascular wall. The initially labile platelet plaque is then stabilized by insoluble fibrin produced upon activation of the coagulation cascade. Inherited genetic factors (gene polymorphisms) and acquired predisposing conditions (such as the concentration and activity of clotting factors) can influence both the composition and the size of an arterial thrombus. Further research is needed to elucidate the functions of blood coagulation proteins and cellular elements that are critical to the pathogenesis of arterial thrombosis. This Review explains mechanisms of pathological arterial thrombus formation and discusses genetic and acquired risk factors of atherothrombosis.