Studies on trials conducted before the use of thrombolysis demonstrated both short- and long-term benefits of beta-blockers, and one meta-analysis of those trials showed a 25% reduction in 1 year mortality. Treatment with beta-blockers was and continues to be recommended for patients after ST elevation myocardial infarction (STEMI), but many patients failed to receive these agents mostly because physicians were unconvinced of their benefit. A similar analysis of the studies in STEMI patients treated with thrombolysis also showed an overall 23% reduction in mortality associated with beta-blocker use in the era of primary percutaneous coronary intervention (PCI). In the present review, we examine the relationship between the pharmacology of beta-blockers and their potential utility in order to review early trials on their post-infarct efficacy and to place these findings in the context of this specific patient population in the era of primary PCI.