This article reviews the treatment of patients with multivessel coronary artery disease (CAD). Percutaneous coronary intervention (PCI) has been challenging coronary artery bypass grafting (CABG) as the gold standard of care for patients with multivessel disease; however, the application of PCI to these patients has been mainly limited by restenosis. Up to the beginning of the 2000s, many large-scale, randomized trials addressed this issue by comparing CABG to PCI with balloon angioplasty or bare metal stents in not only Western countries but also in Asian countries. These studies demonstrated similar rates of all-cause death and myocardial infarction in both groups, although the need for revascularization remained significantly lower in the CABG group. PCI with drug-eluting stents (DES) is safe and may represent a viable alternative to CABG for selected patients with diabetes and multivessel CAD. Moreover, DES implantation under intravascular ultrasound guidance and with fractional flow reserve might have the potential to influence treatment strategy and reduce both DES thrombosis and repeat revascularization. The evolution of DES and advanced vascular imaging would mean that PCI continues to challenge CABG as treatment of choice for patients who need revascularization for a better prognosis.