Primary PCI is an effective reperfusion strategy for acute MI patients, which has evolved significantly in the last decade. While many adjunctive therapies have contributed to its success, substantial obstacles remain before optimal reperfusion can be achieved. Anti-platelet therapy with aspirin, clopidogrel and GP IIb/IIIa inhibitors reduces early ischemic complications, improves microvascular function and, potentially, affects the inflammatory response to ischemic injury. Current anti-thrombin therapy with UFH can be improved with LMWH, and, possibly with direct thrombin inhibitors. A number of important aspects of this strategy, though, need still to be elucidated. We need to optimize microvascular protection before and during PCI in order to capitalize on the myocardial sparing effects of reperfusion therapy. This will be probably achieved with a combination of pharmacological interventions and mechanical emboli protection devices. Improved and more targeted anti-inflammatory therapy should decrease the effects of neutrophil-related reperfusion injury, while a variety of metabolic interventions might preserve myocardial function during ischemia and after reperfusion.