Despite the reduction in stent failure with newer-generation drug-eluting stents, very late stent thrombosis (VLST) remains an unpredictable and potentially catastrophic complication of coronary revascularization procedures and is associated with high morbidity and mortality. Here, we present an updated overview of the latest advances in understanding the causes of VLST. Clinical studies that revealed potential risk factors and pathophysiologic studies on the mechanisms of VLST are discussed. Importantly, novel insights from recent advances in intravascular imaging are included. To date, there is no clinical guideline for VLST treatment. We propose an evidence-based recommendation that an intravascular-imaging-informed percutaneous coronary intervention strategy combined with optimized antiplatelet therapy is the foundation for successful VLST clinical management. Moreover, the future of VLST prevention, such as improved patient risk stratification and advances in addressing late stent failure, are also discussed.