Four thrombolytic comparative trials without a placebo arm have each been conducted in populations of more than 1000 patients: GISSI-2 International, ISIS-3, GUSTO, and INJECT. The treatment strategy associated with use of intravenous heparin and the accelerated regimen of tissue plasminogen activator (t-PA) accounts for the differences between the results of GUSTO and those of the earlier studies of GISSI-2 International and ISIS-3. Using analysis of predefined parameters, it is possible to identify those subsets of patients most likely to benefit from accelerated administration of t-PA. A useful profile of patients at risk for intracranial haemorrhage has also been derived; this profile enhances efficient, sensible, individualized decision making. Results from the angiographic substudy of GUSTO highlight the fundamental importance of early coronary artery patency as a determinant of improved left ventricular function and survival and reaffirm the usefulness of left ventricular function as a surrogate measure for assessing the efficacy of novel reperfusion strategies. In addition, the opportunity to evaluate international differences in practice patterns, coupled with measures of quality of life and return to work, has given new insight into the importance of these issues in the care of patients with acute myocardial infarction. Future investigation must address the challenge of optimal use of resources in assessing novel therapies. Strategies include logistic modelling, surrogate end-points, sample enrichment with high-risk subsets, blended end-points, and uneven randomization.