Although stents mitigate the risk of restenosis, in-stent restenosis (ISR) is still an important clinical problem. ISR usually occurs within the first 3 to 6 months after stenting, with little progression thereafter. ISR progresses through four distinct phases: thrombosis, inflammation, proliferation, and vessel remodeling. Platelets and macrophages play a crucial role in the formation of neointimal tissue via stimulation of vascular smooth muscle migration and proliferation at the injury site. The angiographic pattern of ISR conveys prognostic information on subsequent target vessel revascularization with diffuse proliferative ISR, with total occlusion having the worst prognosis. Stent length and final minimal lumen diameter are additional predictors of ISR. Certain gene polymorphisms may increase the risk of developing ISR. No curative therapeutic modality for ISR has been found; efforts have been focusing on prevention. In this regard, intracoronary radiation therapy has shown the best results, although the promise of several technologies, particularly the drug-eluting stents, will likely result in further reductions (or perhaps irradiation) in the incidence of ISR.