Primary percutaneous coronary intervention of the infarct-related artery is now considered the gold standard for patients with acute ST-elevation myocardial infarction. However, a sizable portion of patients with ST-elevation myocardial infarction have concomitant multivessel disease, which raises important therapeutic and prognostic issues. Indeed, it is still unclear whether percutaneous coronary intervention of the culprit vessel alone is superior, equivalent, or inferior in terms of risk-benefit balance in comparison to a strategy of complete revascularization, with percutaneous coronary intervention of nonculprit vessels as well. The present systematic review provides an updated prospective on the rationale, background, and outcomes of culprit-only versus multivessel percutaneous revascularization in subjects undergoing primary percutaneous coronary intervention. Our findings clearly demonstrate that multivessel coronary disease significantly and adversely impacts on patient prognosis, yet a culprit-only revascularization strategy should be sought after in most cases, unless patient instability or symptoms/signs of residual myocardial ischemia support nonculprit vessel intervention.