For decades, coronary artery bypass grafting (CABG) has been the choice of revascularization strategy for significant left main coronary artery (LMCA) disease. However, with marked technological advances in less invasive percutaneous strategies, such as drug-eluting stents, and potent adjunctive pharmacology, percutaneous coronary intervention (PCI) has been increasingly accepted as an alternative to CABG for selected cases with LMCA disease. The available evidence from randomized clinical trials and adequately sized, real-world registries suggest that hard clinical endpoints (death, myocardial infarction, or stroke) were comparable between two treatment strategies at short- and mid-term follow-up, while higher rate of repeat revascularization are observed after PCI. Current guidelines state that PCI for LMCA disease is reasonable in patients with low to intermediate anatomic complexity and those who are at increased surgical risk. Ongoing large-sized clinical trials comparing newer-generation drug-eluting stents and CABG would provide important clinical insights to guide optimal strategy for patients with significant LMCA disease in the (near) future.