The treatment of unprotected left main coronary artery disease by percutaneous intervention represents a considerable challenge for interventional cardiologists. The American College of Cardiology/American Heart Association guidelines currently recommend surgical revascularization for this disorder and percutaneous interventions have thus far been performed only in exceptional cases, albeit with positive results in some patients. Technical limitations, however, including stent restenosis, limit the application of this technique at present. The availability of drug-eluting stents, which are associated with a reduction in angiographic restenosis, might change this situation. Preliminary results show that the implantation of drug-eluting stents for unprotected left main coronary artery lesions is a feasible and safe approach. Randomized clinical trials comparing the use of drug-eluting stents with coronary artery bypass surgery for unprotected left main coronary artery disease are the next step, but can such trials be contemplated at this stage? In this review we present an overview of the findings to date and discuss the direction that research should now take.