Stent implantation in coronary stenosis has revolutionized the treatment of coronary artery disease. The introduction of antirestenotic drug coatings further improved their efficacy in reducing target vessel revascularizations. With increasing use of drug-eluting stents (DES), stent thrombosis (ST) rose as potentially fatal major complication. Initially, the incidence of ST late after stent implantation seemed to be similar for DES and bare metal stents until several studies proved otherwise in first-generation DES. Since then, the design and components of DES have been changed and new polymers, drugs and different combinations of platelet inhibitors have been introduced to further improve the safety of DES. In this review, the authors focus on the relationship between DES, lesion anatomy, implantation technique and pharmacology to avoid the occurrence of ST. Furthermore, the relationship between dual antiplatelet therapy, bleeding rate and its significant impact on patient outcome is discussed. Finally, some promising future concepts are highlighted.