Experimental models have enhanced our understanding of atherothrombosis pathophysiology and have played a major role in the search for adequate therapeutic interventions. Various animal models have been developed to simulate thrombosis and to study in vivo parameters related to hemodynamics and rheology that lead to thrombogenesis. Although no model completely mimics the human condition, much can be learned from existing models about specific biologic processes in disease causation and therapeutic intervention. In general, large animals such as pigs and monkeys have been better suited to study atherosclerosis and arterial and venous thrombosis than smaller species such as rats, rabbits, and dogs. On the other hand, mouse models of arterial and venous thrombosis have attracted increasing interest over the past two decades, owing to direct availability of a growing number of genetically modified mice, improved technical feasibility, standardization of new models of local thrombosis, and low maintenance costs. To simulate rupture of an atherosclerotic plaque, models of arterial thrombosis often involve vascular injury, which can be achieved by several means. There is no animal model that is sufficiently tall, that can mimic the ability of humans to walk upright, and that possesses the calf muscle pump that plays an important role in human venous hemodynamics. A number of spontaneous or genetically engineered animals with overexpression or deletion of various elements in the coagulation, platelet, and fibrinolysis pathways are now available. These animal models can replicate important aspects of thrombosis in humans, and provide a valuable resource in the development of novel concepts of disease mechanisms in human patients.