Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) system contributes to these processes. The main physiological inhibitor of the fibrinolytic system, plasminogen activator inhibitor-1 (PAI-1), is expressed in murine and human adipose tissues, and high PAI-1 levels predispose to thrombotic complications. The potential role of PAI-1 in development of adipose tissue remains, however, enigmatic. We have used nutritionally induced obesity models in wild-type and transgenic mice to study the role of the fibrinolytic system in the development of obesity. Our main findings are: 1) Obesity is associated with markedly enhanced plasma levels of PAI-1; 2) The effect of PAI-1 on in vivo adipose tissue development is concentration-dependent; 3) PAI-1 does not play a significant role in adipogenesis but may affect angiogenesis; 4). Tissue-type plasminogen activator (t-PA), the main target of PAI-1, impairs adipose tissue development; 5) PAI-1 contributes to the deleterious effect of obesity on the outcome of thrombotic ischemic stroke; and 6) The use of synthetic low Mr inhibitors of PAI-1 may have the potential to reduce obesity. These studies thus support a role for fibrinolytic activity and suggest that its modulation may allow to affect development of adipose tissue.