Percutaneous coronary intervention with drug-eluting stents (DES) is currently the preferred approach to the treatment of obstructive coronary artery disease. Large, randomized trials have demonstrated a significant reduction in the incidence of restenosis and the need for target vessel revascularization following implantation of DES compared with bare-metal stents. Follow-up data extending out to 2 to 4 years have demonstrated efficacy in maintaining luminal patency, but recent concerns regarding potential late adverse effects with DES have been raised. These include aneurysm formation and hypersensitivity reactions, as well as subacute and late stent thrombosis requiring compliance with antiplatelet therapy for protracted periods of time. Evolving strategies to mitigate late adverse events with DES include acceleration of endothelialization, gene therapy targeting pro-healing pathways (ie, nitric oxide donors), smooth muscle cell growth inhibitors, bioabsorbable metal and polymeric stents, and concurrent use of local as well as systemic chemotherapy.