Elevated plasma plasminogen activator inhibitor-1 (PAI-1) level is a core feature of insulin-resistance syndrome (IRS). Atherothrombotic complications in IRS are partly attributed to impaired fibrinolysis caused by increased plasma PAI-1 levels. Although the etiology of IRS is far from being explained, the clustering of inflammation, adipose tissue accumulation and insulin resistance suggests an etiopathological link. Proinflammatory cytokines might regulate PAI-1 expression in IRS; however, more studies are needed to confirm this complex mechanism in humans. Furthermore, modifying PAI-1 expression by PAI-1 inhibitors provides a new challenge and may reveal the true role of PAI-1 in atherosclerotic and insulin resistance processes.