Chronic inflammation within the coronary arteries with infiltration of macrophages into the endothelium results in atherosclerosis. Percutaneous coronary intervention (PCI) remains the standard of care for the treatment of most cases of atherosclerotic coronary artery disease (CAD). Intracoronary stents, either bare metal (BMS) or drug eluting (DES), can successfully treat luminal stenoses within the coronary arteries. Following successful PCI however, neointimal proliferation can develop within the deployed stent. Similar to the pathophysiology of native vessel atherosclerosis there is chronic inflammation within the neointima with infiltration of macrophages, a process called neoatherosclerosis, and can result in in-stent restenosis (ISR) and even acute thrombotic, coronary arterial occlusion following disruption of the neoatheroma. Neoatherosclerosis is a heterogeneous, pathobiological complication of PCI that can present more with angina recurrence or in its most extreme form with an acute coronary syndrome (ACS) In this review article, we will discuss possible mechanisms, clinical challenges, and the future therapies of neoatherosclerosis.