Thrombotic complications of atherosclerotic vascular disease account for the vast majority of myocardial infarctions and strokes. Factors which regulate the thrombotic response to vascular injury are therefore likely to affect cardiovascular events. The elucidation of these factors is of great clinical importance. A major focus of the laboratory is to determine the impact of candidate genes on arterial thrombosis using in vivo mouse models. We have adapted a photochemical model of arterial injury that elicits occlusive thrombosis for use in the mouse and used it to study mice with genetic deficiencies of factors that regulate the fibrinolytic and coagulation cascades. We have also developed a model in which occlusive thrombosis is elicited at the site of an atherosclerotic plaque. These studies indicate that pharmacologic manipulation of key regulatory factors in the coagulation and fibrinolytic cascades may be beneficial to patients with atherosclerotic vascular disease. Recently, we have adapted our mouse models of thrombosis to study the impact of obesity on vascular disease. We found that diet-induced obesity in mice leads to enhanced thrombosis while obesity due to deficiency of leptin is protective against thrombosis. Further studies have demonstrated that leptin is prothrombotic due to its interaction with the leptin receptor on circulating blood elements (plts or monocytes). Since leptin levels rise with increasing adiposity, this may be one of the factors that leads to the increased risk of cardiovascular disease in obese people. Studies have also been initiated to search for novel mouse strain modifiers of obesity-induced vascular complications.