Although the search for the ideal thrombolytic agent continues, recombinant tissue plasminogen activator (t-PA) has proven to be a more potent clot-specific thrombolytic agent than streptokinase. Because t-PA binds directly to the fibrin-plasminogen complex, its effect on circulating fibrinogen is minimized. The development of persistent antibodies or direct induction of hypotension has not been reported, nor has significant activation of the complement system. Unlike streptokinase, urokinase, or anisoylated plasminogen streptokinase activator complex (APSAC), t-PA shows a consistent recanalization rate over time, even as late as 9 hours following onset of chest pain. A number of clinical trials have shown that t-PA is superior in terms of average coronary artery patency rates and survival rates, but bleeding complications with t-PA are similar to those of the other thrombolytic agents. Studies of combinations of t-PA and recombinant prourokinase, as well as of various mutants and hybrids of t-PA, are now underway. The search for viable third-generation thrombolytic agents will have to consider the precarious balance between increasing patency and increasing bleeding complications.