This article discusses the impact of previous clinical observations on the development of the GUSTO-I protocol, particularly the absence of a survival benefit of alteplase (rt-PA) over streptokinase in the GISSI-2/International Study Group and ISIS-3 trials in spite of a higher efficacy for clot lysis. The demonstrated superiority of front-loaded alteplase in this large trial is translated into useful guidelines for the practising clinician. Risk-benefit analysis indicates that, in general, this thrombolytic regimen is most indicated in patients presenting with large amounts of jeopardized ischaemic myocardium in the absence of a particularly increased risk of haemorrhagic stroke. Finally, the impact of this study for future development in the field of acute coronary syndromes is evaluated, more specifically for the design of new trials with new fibrinolytic and antithrombotic agents. These include mutants of alteplase, staphylokinase, direct antithrombins and inhibitors of the glycoprotein IIb/IIIa platelet receptor.