Acute myocardial infarction (AMI) due to unprotected left main coronary artery (ULMCA) occlusion is an uncommon clinical entity, but often leads to severe clinical deterioration, with devastating sequalae including fatal arrhythmias, abrupt and severe circulatory failure, and sudden cardiac death. Recent guidelines have promoted treatment with percutaneous coronary intervention (PCI) as a class IIa recommendation alongside coronary artery bypass grafting (CABG), but the data are still unclear regarding optimal revascularization strategy for patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) with ULMCA culprit. PCI has the advantages of offering rapid reperfusion to critically ill patients, often those with prohibitive risk for surgical revascularization, with acceptable short- and long-term outcomes. Recent studies demonstrate that PCI of the ULMCA is a viable alternative to CABG for appropriate patient populations, including those with ULMCA occlusion and those in cardiogenic shock, Thrombolysis In Myocardial Infarction (TIMI) flow grade 3, and significant comorbidities. A randomized trial comparing PCI with CABG is needed to clarify the ideal revascularization strategy, though the clinical picture of these critically ill patients may preclude such studies.