Uncertainty regarding the appropriate duration of dual antiplatelet therapy (DAPT) with aspirin and a thienopyridine challenges every clinician involved in the care of patients considered for or treated with drug-eluting stents (DES). Despite guideline recommendations for extended (> or =12 months) DAPT following percutaneous coronary revascularization with DES, few data are available to guide clinical decision-making beyond consensus opinion. Yet considering the clinical implications of stent thrombosis (ST) and its unpredictability in late occurring events, comprehensive assessment of the relationship between DAPT duration and ST over the long-term is a focus for DES-related clinical trials and an essential public health measure. Despite the potential for prolonged DAPT to reduce late-term cardiovascular events related to the progression of atherosclerosis, few studies have formally examined the safety and efficacy of extended DAPT and its impact on late ST events. The purpose of this paper is to appraise the existing evidence regarding the relationship between long-term DAPT and late cardiovascular events; address outstanding (and unstudied) dilemmas related to DAPT in DES-treated patients; and propose considerations for both trial design and clinical practice.