Although in-stent restenosis is the result of neointimal hyperplasia, mechanical problems (e.g. stent underexpansion) that occurred during implantation may result in restenosis at follow-up. The treatment of in-stent restenosis, begins with identification of these occult mechanical problems. Thereafter, in-stent restenosis can be treated with PTCA, atheroablation, or additional stent implantation; it is nuclear which technique is superior. Not all in-stent restenosis lesions have a similar risk of recurrence. Recurrence appears to depend on several markers of biologic activity: focal vs diffuse in-stent restenosis, the first episode vs recurrent in-stent restenosis, and early vs late recurrence. Vascular brachytherapy has emerged as the most promising way to treat high-risk lesion subsets.