Favorable outcomes in multiple randomized trials have resulted in the widespread adoption of drug-eluting stents (DES) during percutaneous coronary intervention (PCI). However, reports of increased stent thrombosis—possibly with increased rates of late death and myocardial infarction (MI)—along with the requirement of an extended course of clopidogrel with DES, have resulted in uncertainties as to which patients should receive DES instead of bare-metal stents (BMS). In most patient and lesion subsets, DES significantly reduce neointimal proliferation (resulting in decreased angiographic restenosis), recurrent angina and ischemia, and the need for subsequent revascularization procedures. DES “off-label” indications include use in patients with multiple lesions and multiple vessels, lesions showing long diffuse disease, very small or very large vessels, true bifurcation lesions, thrombotic lesions, and conditions such as acute MI and chronic total occlusions. For now, pending more data, the risks and benefits of DES for off-label indications must be carefully considered on an individual patient basis.