Forty to 60% of ST-elevation myocardial infarction (STEMI) patients present with multivessel coronary artery disease, identified during primary percutaneous coronary intervention (pPCI) of the culprit lesion. At present, data about revascularization of non-culprit coronary lesions are conflicting. Nevertheless, patients with multivessel coronary artery disease have a worse outcome. Recently, several randomized controlled trials and meta-analyses compared a strategy of culprit-only revascularization vs complete revascularization (during pPCI or staged PCI of the non-culprit lesion). The majority of data show a potential benefit of complete revascularization, in particular a reduction in the composite endpoint of major adverse cardiac events, in absence of certain data regarding long-term mortality and reinfarction. Besides, it is still controversial the optimal timing of complete revascularization (during pPCI or staged PCI), as well as the best method for evaluating the lesions to be treated (angiographic vs functional assessment of ischemia). Considering all these data, the only tested and safe approach to treat multivessel coronary artery disease patients remains optimization of medical therapy with long-term prescription of newer antiplatelet agents (ticagrelor and prasugrel) and aggressive lipid-lowering therapy (LDL <70 mg/dl). At the same time, a complete coronary revascularization strategy with PCI, especially guided by ischemia and based on patient lesions and comorbidity, may further improve outcomes.