Endothelial-to-mesenchymal transition (EndMT) is a cellular reprogramming mechanism by which endothelial cells acquire a mesenchymal phenotype. EndMT is associated with fibroproliferative diseases, such as cancer progression and metastasis and cardiac and kidney fibrosis, and this condition has been extensively investigated over the past decade. Recently, studies showed that EndMT contributes to the initiation and progression of atherosclerotic lesion and plaque destabilization. Unstable atherosclerotic plaque rupture and subsequent thrombosis are the main pathological causes of acute cardiovascular events. EndMT is plastic and reversible. Therefore, our enhanced understanding on the mechanisms controlling EndMT and its roles in the atherosclerosis plaque progression and instability may provide a basis for the development of novel therapeutic strategies to stabilize and reverse atherosclerotic plaques.