Despite the impressive benefits obtained following the introduction of the drug-eluting stent, safety concerns have been raised over their long-term safety with particular regard to stent thrombosis. Various mechanisms such as delayed endothelialization, local hypersensitivity and endothelial dysfunction owing to the durable polymer coating and/or the drug itself have been suggested as possible causes of this phenomenon. Therefore, to address these concerns, a newer-generation of drug-eluting stents has been developed and they are currently undergoing preclinical and clinical evaluation in order to increase both the safety and biocompatibility by optimizing the three major components of drug-eluting stents: the stent platform, the polymer and the drug. This article critically reviews the key clinical trials and the current status of these new coronary devices as well as preventing future perspectives for their continued development.