Obesity and diabetes once considered 'rich man's diseases' are one of the biggest public health challenges of the 21st century. Obesity being a gateway to diabetes is a global problem. The supporting statistics are alarming since diabetes is reaching pandemic proportion all over the world. Eighty percent of all patients with diabetes live in developing countries. In this review we describe the role of plasminogen activator inhibitor type one (PAI-1) in the pathology of obesity and diabetes and its potential to be a target in therapy. PAI-1 is the fast acting and specific inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and consequently of fibrinolysis. In obesity and diabetes it has been linked to the increased incidence of thrombosis. However, PAI-1 is also involved in the regulation of other proteins engaged in hemostasis. These molecules include transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α), angiotensin II and interleukin 6 (IL-6), all of which up-regulate PAI-1 in various cell types or can be up-regulated by PAI-1. Thus, PAI-1 plays a critical role in the insulin resistance syndrome, which leads to type 2 diabetes mellitus, and is associated with its side effects such as an increased risk of diabetic nephropathy, atherosclerotic cardiovascular disease and others. Thus inactivating of PAI-1 or increasing its clearance can alleviate the burden of obesity and diabetes.