First-generation drug-eluting stents (DES) have brought major improvements in results of percutaneous coronary intervention (PCI). However, there is currently debate on the safety of these first-generation DES, given the potential for late stent thrombosis, especially after discontinuation of dual antiplatelet therapy. Second-generation DES, such as zotarolimus- (Endeavor) and everolimus-eluting stents (Xience V), have recently become available in the USA and/or Europe. Indeed, the Xience V stent holds the promise of superior anti-restenotic efficacy as well as long-term safety, yet there is uncertainty on its risk-benefit balance. Authors conducted a systematic review of basic science and clinical evidence on the Xience V, by thoroughly searching PubMed and online databases (updated September 2007). They also compared the clinical results of Xience V vs paclitaxel-eluting stents (Taxus) and sirolimus-eluting stents (Cypher) by means of direct and indirect comparison meta-analysis. A total of three clinical studies has been retrieved focusing on Xience V, however both most recent and important trials were still unpublished. The first trial compared Xience V vs bare-metal stents, whereas the other two randomized trials compared Xience V vs Taxus. Direct meta-analysis of Xience V vs Taxus showed that Xience V was significantly superior to Taxus in preventing binary angiographic restenosis and target lesion revascularization (P<0.05 for both). Indirect comparison between Xience V and Cypher, exploiting a recent 16-trial large meta-analysis, showed that Xience V was at least as effective as Cypher in preventing target lesion revascularization (P=0.12). Everolimus-eluting stents (Xience V) appear as a major breakthrough in coronary interventions, and superior efficacy has already been demonstrated in comparison to paclitaxel-eluting stents (Taxus). Data available to date also suggest that Xience V is at least as effective as sirolimus-eluting stents (Cypher). Whether long-term results and direct comparison to Cypher will also be favorable remains to be established by future clinical trials.