Coronary artery in-stent restenosis (ISR) is driven by neointimal hyperplasia and neo-atherosclerosis in previously placed stents. Drug eluting stents (DES) have been adopted as first line therapy for the initial episode of ISR. However, recurrent ISR has limited durable salvage options. In this article we review the pathophysiology, incidence, and management options of recurrent DES- ISR.