Plasminogen Activator Inhibitor-1 (PAI-1) is a member of the evolutionarily conserved serine protease inhibitor (SERPIN) family, and a potent and rapid-acting inhibitor of both of the mammalian plasminogen activators. Organismal homeostasis requires physiological levels of endogenous PAI-1 and increased PAI-1 production guides the onset and progression of numerous human diseases and contributes to the multimorbidity of aging. Both chronological and stress-induced accelerated aging are associated with cellular senescence and accompanied by marked increases in PAI-1 expression in tissues. Recent studies suggest that PAI-1 is not only a marker but also a key mediator of cellular senescence and organismal aging. Here, we review the significance of PAI-1 as a bonafide marker as well as a critical mediator of cellular senescence associated with aging and aging-related pathologies.