Recent interest has shifted from infarct artery patency to microvascular perfusion in the evaluation of patients with acute myocardial infarction (AMI). Microvascular dysfunction occurs in a substantial proportion of patients, despite aggressive therapy with thrombolytic agents and/or percutaneous mechanical revascularization techniques. Patients with impaired microvascular perfusion after immediate reperfusion therapy have an adverse clinical prognosis. Recent studies have extended our understanding of the pathophysiology of this so-called no-reflow phenomenon, focusing on the critical roles of platelet and inflammatory mediators leading to microvascular obstruction and reperfusion injury. Moving beyond the Thrombolysis in Myocardial Infarction (TIMI) flow grade system, new techniques have been developed to assess microvascular perfusion, including TIMI frame counting, angiographic myocardial perfusion grading, myocardial contrast echocardiography, Doppler flow wire studies, nuclear scintigraphy, and magnetic resonance imaging. Armed with a greater understanding of the primary mediators of microvascular dysfunction, these tools may identify improved therapy directed at optimizing myocardial perfusion in patients with AMI.