Reperfusion therapy of the infarct-related artery (IRA) with primary percutaneous coronary intervention is the cornerstone for the treatment of patients with ST-elevation myocardial infarction (STEMI). However, up to 30% of STEMI patients present a multi-vessel coronary artery disease. Several methods are now available for the assessment of functional severity of a coronary stenosis both for IRA and non-culprit coronary lesions. The functional assessment of the IRA has mainly a prognostic implication in terms of major adverse cardiovascular events, recovery of left ventricular function and evaluation myocardial viability. Conversely, the functional assessment of the non-culprit coronary lesions has a fundamental role to guide staged revascularization. The aim of this review is to revise the most validated methods to perform the functional assessment of both culprit and non-culprit lesion in ST-elevation myocardial infarction.