The 1980s has been a critical decade for the management of acute myocardial infarction (MI) because of the concentration in a very short time span of innovative results produced by a new generation of trials, in which thrombolysis has been the preeminent topic. The message coming from the results in the more than 50,000 patients included in the five key trials is simple and clear: thrombolysis, of any type, is the cornerstone of acute treatment of MI, and it works well to produce a very favorable epidemiologic picture. In the GISSI-2 trial, the nationwide adoption of a package of recommended treatments centered on thrombolysis for the overall population of patients with an acute MI has produced a relevant modification of the natural history of the disease, reducing the in-hospital mortality by about 40% in few years (from 13% to 8.8%). In particular, in the great majority of cases (patients aged less than 70 years in Killip class I with a first acute MI), the mortality has gone down to 3%, making a further reduction very hard to obtain with new drugs or strategies. In this context, we will discuss the concept of the relevance for clinical practice of obtaining even greater patency rates with new thrombolytic agents (hopefully more efficient and safe) or with new combinations of traditional agents.