When compared to bare metal stents (BMS), drug-eluting stents (DES) are associated with a dramatic reduction in restenosis and target lesion revascularization. However, the benefit of DES is limited to restenosis, and DES utilization does not translate into reductions in death or myocardial infarction. Additionally, concern exists regarding the long-term safety of DES, as there appears to be a small but real increase in late (LST) and very late stent thrombosis (VLST), seen particularly after the discontinuation of antiplatelet therapy. The specter of LST and VLST has curtailed enthusiasm for widespread DES utilization mandating critical appraisal of DES and the optimal role they play in percutaneous coronary intervention. The incidence of DES thrombosis is debated and varies somewhat by definition. The mechanisms are multifactorial, and involve patient, lesion, stent and physician related factors. Some of these factors are modifiable at the physician-patient level, while others are not. This review focuses on DES thrombosis, with particular attention paid to the definitions, incidence, mechanisms and clinical implications.