The field of interventional cardiology has significantly evolved over 40 years by overcoming several challenges. The introduction of first-generation drug-eluting stents significantly reduced the rates of restenosis, but at the expense of an increase of late stent thrombosis. Prolonged antithrombotic therapy reduced rates of stent thrombosis, but at the cost of increased bleeding. Although the advent of second-generation drug-eluting stents subsequently reduced the incidence of late stent thrombosis, its permanent nature prevents full recovery of vascular structure and function with accordant risk of very late stent failure. In the present era of interventional cardiology, the tradeoff between stent thrombosis, restenosis, and bleeding presents as a particularly complex challenge. In this review, the authors highlight major contributors of late/very late stent thrombosis while targeting stent restenosis, and they discuss evolutionary advances in stent technology and antiplatelet therapy, to further improve upon the care of patients with coronary artery disease.