A classical perspective of cardiovascular risk does not adequately account for all of the cardiovascular events associated with obesity and diabetes. The combination of hypertriglyceridemia, glucose intolerance and inflammation is linked with increased production of the primary inhibitor of endogenous thrombolysis, plasminogen activator inhibitor-1 (PAI-1). Recent data suggest that PAI-1 contributes directly to the complications of obesity, including type 2 diabetes, coronary arterial thrombi, and may even influence the accumulation of visceral fat. Therefore, direct inhibition of PAI-1 might not only provide a new therapeutic strategy for reducing cardiovascular risk, but may also have beneficial effects on obesity and insulin resistance.