Drug-eluting stents (DES) have emerged as an improved alternative to bare-metal stents by demonstrating reduced rates of restenosis and target lesion revascularization. This emergence has led to the unrestricted use of DES for various indications and lesions, and subsequently revealed DES in-stent restenosis as a novel interventional therapeutic dilemma. Recent insights regarding the patho-physiological processes and therapeutic alternatives have added to the accumulated knowledge regarding the appropriate approach to this phenomenon. This review aims to detail the mechanism and clinical presentation of, and therapeutic strategies for, the treatment of DES in in-stent restenosis.