In-stent restenosis is the limiting entity following coronary stent implantation. It is associated with significant morbidity and cost and thus represents a major clinical and economical problem. World-wide, approximately 250,000 instent restenotic lesions per year have to be dealt with. The clinical picture associated with in-stent restenosis is similar to the one caused by de-novo stenoses in atherosclerotic coronary artery disease, yet differs distinctly from those with respect to the frequency and severity of symptoms, angiographic and hemodynamic peculiarities of the restenotic lesions and clinical end-points. In-stent restenosis has been recognised as a problematic issue. While relatively easily to handle in the catherization laboratory, the long-term outcome is critically limited by a repeat restenosis rate of 50% regardless of the mechanical angioplasty device used. Much more favourable results were reported for intracoronary brachytherapy, with a consistent reduction of the incidence of repeat in-stent restenosis by 50%. The most promising data have been generated by the use of drug-eluting stents, with restenosis rates and clinical outcomes almost as favourable as in de-novo coronary lesions. Yet, drug-eluting stents are under critical debate due to the still unresolved question of subacute stent thrombosis. This review outlines the epidemiology, the predictors and the diagnostic work-up of in-stent restenosis and provides detailed information on the various treatment options for its prevention and therapy.