The introduction of the drug-eluting stent has raised concerns regarding the occurrence of stent thrombosis (ST), particularly late (and very late) thrombosis. This renewed attention shows that ST remains a major concern after implantation of both bare metal and drug-eluting stents. Cardiologists should be aware of this dreadful complication, because it is associated with substantial morbidity and mortality. Numerous clinical, procedural, and angiographic risk factors have been identified. Moreover, the influence of novel determinants, such as high on-treatment reactivity, genetic predisposition, and the stent's direct effects on the (healing of the) vessel wall, now are recognized. Consequently, the pathophysiology of ST has evolved into a complex multifactorial model. This broader understanding of the pathophysiology of ST enables cardiologists to perform extensive risk stratification to identify patients at higher risk and provides clues to important treatment options. The core of primary prevention after stent implantation, as well as secondary prevention after ST, should consist of a) the prevention of modifiable risk factors and b) optimal individualized treatment for each patient. Future developments, such as genetic bedside testing, point-of-care platelet testing, and sophisticated imaging modalities, might aid in this approach.