The blood coagulation and the fibrinolytic (or plasminogen/plasmin) systems determine the balance between the formation and dissolution of blood clots, but in addition contribute to the pathogenesis of various cardiovascular disorders such as thrombosis, atherosclerosis, and restenosis. Furthermore, they participate in a variety of other (patho)biological processes such as embryonic development, reproduction, wound healing, cancer, and brain function. Two recently developed technologies, gene targeting and gene transfer, that allow manipulation of the genetic balance of these proteinase systems in a controllable manner have allowed a more definitive elucidation of the biological role of these systems. This review summarizes the insights that have been obtained from the gene targeting studies and discusses the use of adenovirus-mediated transfer of fibrinolytic genes to study and possibly to develop novel strategies for the treatment of restenosis and thrombosis.