The blood coagulation mechanism in general and the plasminogen system in particular contribute to malignant growth and dissemination in complex ways. This article reviews the extensive literature that has accumulated over the past half-century on effects of plasminogen activation on the natural history of experimental animal and human malignancy. Although the potent enzymes generated upon plasminogen activation may have a direct effect on tumor cells, it is more likely that their mechanism of action is related to disruption of the tumor cell-extracellular matrix interaction. These observations suggest novel approaches to the experimental therapy of cancer.