The use of drug-eluting stents (DES) has rapidly expanded from lower-risk, singlelesion procedures to include a broad spectrum of high-risk patients and complex lesions. For 4 complex patient subgroups, emerging data suggest that DES might offer an advantage for reducing late clinical restenosis. In ST elevation myocardial infarction, early registry reports are promising, with no evidence to date for an increased incidence of subacute stent thrombosis and significant trends for less restenosis. For chronic total occlusions, early, small clinical series show that DES might have unprecedented long-term patency. Initial registries of DES for in-stent restenosis reveal striking reductions in late loss and restenosis, compared with brachytherapy historical controls. The use of DES in saphenous vein graft lesions is increasing, and early registry results show a very acceptable incidence of thromboembolic complications and major adverse cardiac events. Important data regarding much larger groups of these patient cohorts will emerge over the next year, to help guide the broader application of DES in “real-world” practice.