Since the inception of percutaneous coronary intervention, restenosis has been considered a significant problem. Although drug-eluting stents (DES) have reduced rates of in-stent restenosis (ISR) compared with bare metal stents across all lesion subsets, ISR has not been abolished. DES efficacy has been limited by suboptimal polymer biocompatibility, efficacy of pharmacological agents, in vivo pharmacokinetic properties, and local drug resistance and toxicity. While the first two DES to be manufactured (sirolimus- and paclitaxel-eluting stents) have the longest clinical follow-up, extensive data are now also available on zotarolimus- and everolimus-eluting stents. The uptake of biolimus-eluting stents has recently increased in clinical practice. Although the low frequency of DES ISR makes it difficult to investigate this condition fully, many studies have examined the mechanism, incidence, predictors, and optimal treatment of DES restenosis. This review discusses the data relevant to DES restenosis and the perspective on the current treatment of this condition.