Thrombolytic therapy has galned increasing acceptance in the clinical arena in recent years, but is fraught with three primary problems: delays in time to lysis, reocclusion, and haemorrhage. Inasmuch as the platelet is a critical determinant of thrombosis and, at the same time, interacts with molecular elements important in fibrinolysis, this anuclear cell plays a central role in the outcome of thrombolytic therapy. Platelet-rich thrombi are less sensitive to thrombolysis than platelet-poor thrombi, and reocclusive thrombi are richer in platelets than are thrombi that form de novo. Moreover, upon exposure to the fibrinolytic milieu, the platelet becomes transiently activated and, consequently, retards the progress of the lytic process; with continued exposure, however, the platelet becomes progressively inhibited and, as a result, bleeding times prolong and haemorrhagic risk increases. The molecular events that lead to these changes in platelet function during thrombolysis are, indeed, complex, and serve as the primary focus of this review.