Contemporary management of coronary artery disease relies increasingly on percutaneous techniques combined with medical therapy. Although percutaneous coronary intervention (PCI) can be performed successfully in most lesions, several difficult lesion subsets continue to present unique technical challenges. These complex lesions may be classified according to anatomic criteria, including extensive calcification, thrombus, and chronic occlusions, or by location, such as bifurcations, saphenous vein grafts and unprotected left main. PCI of these lesions often requires novel devices, such as drug-eluting stents, hydrophilic guidewires, distal protection balloons or filters, thrombectomy catheters, rotational atherectomy, and cutting balloons. An integrated approach that combines these devices with specialized techniques and adjunctive pharmacologic agents has greatly improved PCI success rates for these complex lesions.