Comparative preclinical histologic studies remain the most effective method for assessing the healing characteristics of vascular stents. The 2 most commonly used animal models to assess vascular responses to stent implantation are the porcine coronary artery and the rabbit iliac artery. Neither model alone is comparable to the human response to the implantation of a drug-eluting stent (DES). In the rabbit model at 28 days, the pathologies of the zotarolimus-eluting stent (ZES), the paclitaxel-eluting stent (PES), the sirolimus-eluting stent (SES), and a bare metal stent (BMS) were assessed. There was less inflammation with the ZES than with the SES or PES, and there were uncovered struts with the SES and PES but not with the ZES and BMS. In the pig model at 30, 90, and 180 days, the pathologies of the ZES, SES, and BMS were assessed. At 30 days, the thickness of neointima and the grade of inflammation were less with the SES than with the ZES and BMS, but at 90 and 180 days, the measures increased for the SES and were greater than those with the ZES and BMS, whereas the measures for the ZES and BMS did not change over time. In the rabbit model, the endothelialization of overlapping the SES, PES, and ZES was assessed. There was significantly greater endothelialization in the area above stent struts in the overlapping segment for the ZES than for the SES (p = 0.028). The level of endothelialization for the PES was less than that for the ZES, but the difference was not significant. Because arterial healing is multifactorial, it is extremely important that the next generation of DESs undergo preclinical testing in pig and rabbit models to examine endothelialization, inflammation, release kinetics, and neointimal reduction to establish the safety of these devices in humans.