Stent thrombosis (ST) is a rare but severe complication of coronary procedures with high mortality, high relapse rate and a very complex pathophysiology. An individual's susceptibility to ST is multifactorial and results from interactions between clinical factors, endothelial biology, hypersensitivity and/or inflammatory reactions, blood rheology, platelet reactivity, clotting factors, physical and mechanical properties of the stent and from the effects of these different factors on the fluid dynamics of blood flow. Since the introduction of stents 32 years ago, continuous improvements in our understanding of the pathophysiology of ST have triggered important advances, including new therapies, new technologies and an increased awareness of the implications of implantation techniques. Furthermore, advances in medical imaging and in the mathematical processing of this information have allowed a more detailed assessment of the mechanisms of ST at the time of its onset. Evidence shows that addressing the risk factors for ST leads to a substantial reduction in its incidence, both early and late after stent implantation. A better knowledge of the mechanisms of this complication is, however, necessary to direct the choice of the most appropriate strategy for its prevention and treatment.