Treatment for ST- elevation acute coronary syndromes (acute myocardial infarction: AMI) has advanced rapidly in the last decade with major improvements in early fibrinolytic therapy (FT), primary percutaneous interventions (PCI) with the aid of platelet glycoprotein IIb/IIIa inhibitors. Recent interest has shifted from infarct related artery (IRA) patency to microvascular perfusion in the evaluation of patients with AMI. It is well known that establishing epicardial patency after AMI (TIMI 3 E) is not synonymous with tissue-level perfusion (TIMI 4M). Microvascular dysfunction due to the roles of platelet and inflammatory mediators in the no-reflow phenomenon occurs in a substantial proportion of patients despite thrombolytic therapy or PCI procedures. Techniques are now available that measure real tissue-level perfusion and also therapy is directed to optimize myocardial perfusion in patients with AMI. Despite advances, contemporary FT strategies with the combination of platelet glycoprotein IIb/IIIa inhibitors restore normal coronary flow (TIMI 3) in the IRA in only 50-75% and PCI achieves TIMI 3 flow rates in 90-95%, but only with modest reductions in mortality, but with significant reductions in rethrombosis of the IRA or stents, reinfarctions and in some patients with benefits in ventricular dysfunction. Therefore moving beyond the importance of TIMI 3 flow, the TIMI 4 flow, or improving tissue-level perfusion in the setting of AMI seems to be the paradigm for the treatment of ST-elevation acute coronary syndromes.