Drug-eluting stents (DES) are designed to release pharmacological agents into the vessel wall in order to inhibit the response to injury causing restenosis, i.e., vascular smooth muscle cell migration and proliferation. Once deployed, however, these substances exert many biological effects in the coronary circulation; their action is indeed not confined to inhibition of vascular smooth muscle cells, but extends to other cell types such as endothelial cells. Both rapamycin and paclitaxel decrease endothelial cell migration and proliferation; moreover, they induce tissue factor expression through specific interaction with signal transduction mediators. As both effects would lead to an increased thrombogenic potential of DES, they appear particularly important in light of a possibly increased risk for stent thrombosis with DES as compared to bare-metal stents. This aspect is further highlighted by the observation that DES also decrease proliferation, differentiation, and homing of endothelial progenitor cells, which are believed to contribute to reendothelialization after stent implantation. Furthermore, both rapamycin and paclitaxel have been demonstrated to induce endothelial dysfunction in the coronary vasculature distal to the stent. Finally, the polymer used for DES may be associated with hypersensitivity reactions, which may, at least in some cases, favor stent thrombosis. This review will discuss the biological effects of DES in the coronary vasculature.