Whether induced surgically or by hypertension, infections, extreme heat, or caustic chemicals, tissue injury invariably leads to vasodilatation, with subsequent leakage of plasma proteins into the connective tissues, rapid activation of the coagulation cascade, and deposition of fibrin. A central paradigm in the field is that the fibrin is organized into a “provisional fibrin matrix,” which acts as a road map to direct the migration of invading cells. Leukocytes and possibly fibroblasts migrate into the area and elaborate cytokines which, in turn, stimulate resident cells to synthesize and deposit collagens and other insoluble fibrillar components into the evolving extracellular matrix (ECM). Fibrotic disease occurs when normal control of this process is compromised and excess fibrous material accumulates in the tissues. It is generally assumed that the persistence of fibrin in the matrix promotes fibrosis, and that the extent of fibrosis is limited by proteinases that remove the fibrin (ie, the fibrinolytic system). In a recent issue of the JCI, Hattori et al.(1) affirm previous suggestions that plasminogen activator inhibitor-1 (PAI-1) promotes pathological fibrosis but challenges the concept that fibrin is required.