Restenosis is defined as a reduction in lumen diameter after percutaneous coronary intervention (PCI), either with or without stent implantation. In case of no-stent strategy, it usually consists in vessel remodeling and elastic recoil (ER); otherwise it is determined by an excessive tissue proliferation in the luminal vessel of the stent called “neointimal proliferation”, or by a new-occurring atherosclerotic process called “neoatherosclerosis”. From the clinical point of view, restenosis is often associated with the recurrence of angina symptoms or an acute coronary syndrome, and may drive to a reintervention either with coronary artery bypass or re-PCI. This reintervention is usually called target lesion revascularization (TLR). However, we have to distinguish between those revascularizations that are performed for an incidental finding during angiography (angiographic-driven TLR) and those that are clinically-driven because of symptoms or evidence of a significant ischemia during provocative tests. In-stent restenosis (ISR) has always been considered the “enemy” for the interventional cardiologists, thus many technical improvements in the last 20 years aimed at reducing its occurrence: firstly, newer generation bare metal stents (BMS), then drug-eluting stents (DES) and finally drug-coated balloons (DCB). Moreover, ISR is an independent predictor for mortality during follow-up, together with other relevant clinical factors as age, sex, diabetes mellitus, smoke habit, previous by-pass surgery, and left ventricular ejection fraction.