In-stent thrombosis remains to bo an uncommon but dreadful complication of coronary angioplasty manifesting as sudden death or acute coronary syndrome. Drug-eluting stents (DES) proved to be an effective approach in the prevention and treatment of restenosis across a broad spectrum of lesion and patient subsets. Considerable concerns over this technology were raised when a modest increase in the incidence of very late in-stent thrombosis was demonstrated in DES-treated patients which in some trials even translated into higher mortality and myocardial infarctions compared with bare metal stenting (BMS). Unfortunately, DES not only suppress neointimal formation, but also impair the vessel healing process. Delayed and incomplete endothelialization is frequently observed after DES application. Increased blood thrombogenicity due to the prothrombotic effects of eluting drugs and inadequate platelet inhibition along with altered blood flow through remodeled arteries with dysfunctional endothelium contribute to late DES thrombosis. However, a large amount of data from randomized trials suggest that DES when used on label are not associated with unfavourable clinical outcomes. In these patients DES are probably responsible for a slightly elevated risk of late thrombotic events and simultaneously decreased rates of restenosis-related myocardial infarctions and deaths compared with BMS. The potential benefits and risks of DES off-label stenting are yet to be assessed. Since insufficient platelet inhibition was reported as the strongest predictor of DES thrombosis, the necessity of prolonged dual antiplatelet therapy has constituted a major limitation of this device. Therefore, DES implantation should be particularly avoided in non-compliant patients, in those who are scheduled for major surgery requiring premature discontinuation of dual antiplatelet therapy, and in persons who are at high risk of bleeding. Elective operations in DES patients are suggested to be postponed until 12 months after stenting, while dental procedures, when needed, may be performed on dual antiplatelet treatment. Although recent European and American guidelines recommend dual antiplatelet therapy after DES placement for 6-12 and 12 months, respectively, its optimal duration is a matter of ongoing debate. Subsequent generations of DES developed for a better safety profile as well as novel technologies dedicated to facilitate endothelialization are currently under investigation. Finally, caution is advised in the choice of the particular device for each patient.