The aim of this article is to review the treatment of patients with multi-vessel coronary artery disease. Percutaneous coronary intervention (PCI) has been challenging coronary artery bypass grafting (CABG) as the gold standard of care for patients with multi-vessel disease; however, the application of PCI to these patients has been mainly limited by restenosis. Up to the late 1990s, numerous large-scale, randomized trials addressed this issue comparing CABG to PCI with balloon angioplasty or bare-metal stents. These studies demonstrated similar rates of death and myocardial infarction in both groups, while the need for revascularization remained significantly lower in the CABG group. Drug-eluting stents (DES) have dramatically reduced restenosis and repeat revascularization rates. CABG has also progressed with improvements in perioperative management, a higher use of arterial grafting, and advanced techniques with the implementation of minimally invasive and off-pump surgery as options. Therefore, the results of previous trials in the pre-DES era can no longer be extrapolated into the ''real world''. As intermediate steps preceding a fully-fledged, randomized trial, several trials have compared PCI with DES and the historical control of CABG, but the results are still inconclusive. Several dedicated randomized trials are currently ongoing to compare PCI with DES and CABG using contemporary techniques. Until the results of these randomized trials are presented, the choice for each strategy should be based on the patients' individual risk and anatomy.