Thrombolytic therapy dates back to animal studies performed in the early 1940s, although clinical trials did not begin until the early 1980s. Many large, placebo‐controlled trials conclusively recorded improved survival with thrombolytics in the treatment of acute myocardial infarction. However, only recently did clinical trials compare tissue plasminogen activator (tPA) and streptokinase (SK), and only one study showed a difference in mortality between them. This discrepancy, in part, led to the open‐artery hypothesis that early and sustained infarct‐related artery patency improves outcome. This theory was tested in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO‐I) study. The angiographic substudy of GUSTO‐I provided strong evidence for the relationship between 90‐minute thrombolysis in myocardial infarction (TIMI) grade 3 flow and lower mortality. However, despite significantly higher 90‐minute TIMI grade 3 flow (54% vs 32%) with accelerated tPA versus SK plus intravenous heparin, the absolute difference in mortality rate was less than 1%. The recently completed GUSTO‐III trial compared accelerated tPA with reteplase (rPA). Based on the open‐artery hypothesis and previous data showing an absolute difference of 15% in 90‐minute TIMI grade 3 flow between the agents, it was anticipated that mortality would be lower with rPA than with accelerated tPA. The GUSTO‐III study showed no significant difference in 30‐day mortality for the agents (7.47% vs 7.24%, p=0.61), respectively. These results raise questions about the validity of the hypothesis: if 90‐minute TIMI grade 3 flow is such a strong predictor of mortality, why is there not a greater difference in mortality rates for thrombolytic agents?