Chick, hamster, mouse, and rat embryo fibroblast cultures, transformed by either DNA or RNA viruses, show fibrinolytic activity under suitable conditions of growth and in appropriate media; normal counterpart cultures do not. The fibrinolysin is produced by the interaction of two protein factors: one of these, a cell factor, is released by transformed cells and accumulates in the medium when cultures are incubated in the absence of scrum. The second factor, the serum factor, is a specific protein that is present in sera of many avian and mammalian species, including man. Not all sera yield fibrinolysin on interaction with any given transformed cell factor, and the spectrum of activating sera is distinctive for each cell factor. This pattern appears to be determined by the cell type, rather than by the transforming virus. An important role for the fibrinolysin in oncogenic transformation is suggested by the following correlations. (a) The initial appearance of fibrinolysin precedes the morphological change after the transfer to permissive temperatures of chick fibroblast cultures infected with a temperature-sensitive mutant of RSV. (b) The initiation of fibrinolysis and of morphological change both require the synthesis of new protein, but not the synthesis of either DNA or rRNA. (c) The activity of the fibrinolysin is correlated with the retention of abnormal morphology in hamster cells transformed by SV-40. (d) The sera of normal chicks effectively activate fibrinolysis with the cell factor from transformed chick cells. In contrast the sera of chicks with RSV tumors do not; these contain an inhibitor of the fibrinolytic activity.