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Drug-eluting stents (DESs) are known to reduce in-stent restenosis rate, compared with bare metal stents (BMSs). Stent thrombosis, one of the most dangerous complications of DES, has emerged as a major concern. This issue has limited the use of DES in unstable coronary artery disease till recent years. In fact, acute coronary syndrome (ACS) and the subsequent activation of the hemocoagulative pathway could represent a prothrombotic environment, thus limiting the use of DES in this situation. Nowadays, there is increasing evidence in literature of similar stent thrombosis rates both for BMS and DES in ACS, and most interventional cardiologists are confident with the use of DES in ACS. The aim of this article is to review the current literature on this topic in order to compare first-generation and second-generation DES vs. BMS as concerns safety and efficacy.