Population trials on myocardial infarction have produced significant advances in therapeutic results. The first clearly stated aim of the GISSI-2 protocol was the assessment of the overall benefit to a population attributable to the application of a package of pharmacological treatments (thrombolysis, intravenous beta blockade, and oral aspirin) shown effective in reducing mortality in large-scale randomized clinical trials. At variance with the classical concept of trials, a clinical epidemiological interest came first: The comparison between drugs was considered a main target of the investigation only within that broader framework, and was explicitly formulated as the direct confrontation between two concepts or two generations of thrombolysis. A selective, highly efficient, and specific new thrombolytic agent, tissue plasminogen activator (tPA), is compared with streptokinase with the expectation that the more selective approach could enhance the benefits of specificity, drastically limiting the systemic risks aspects (hemorrhagic complications). The main results of GISSI-2 are summarized. GISSI-2 may be considered a reliable window on the epidemiology of AMI in a whole country. There are implications for the transfer of these clinical findings into public health applications and for the choice of future research priorities.