Treatment of in-stent restenosis (ISR) remains problematic despite the widespread application of drug-eluting stents (DES). Challenging lesion cohorts such as diffuse ISR and restenosis after failed intracoronary radiation therapy (IRT) maybe best treated with DES. The overall benefit of DES appears inferior to their utility in treating de novo coronary lesions. Randomised trials comparing DES and IRT will soon be available to determine the optimal therapy for ISR. The challenge to treat ISR in the DES era is the next frontier of interventional cardiology.