Atherosclerotic cardiovascular disease (ASCVD) is a chronic inflammatory disease of the arterial walls characterized by accumulation of lipoproteins that are insufficiently cleared by phagocytes. Following the initiation of atherosclerosis, the pathological progression is accelerated by engagement of the adaptive immune system. Recently, several research groups reported that atherosclerosis triggers the breakdown of tolerance to self. This phenomenon was discovered by using single-cell RNA sequencing in conjunction with T cell receptor (TCR) sequencing. I will discuss the discovery papers, evaluate the supporting evidence, map out potential future work and discuss the clinical significance of this breakthrough. Rational approaches aimed at re-establishing immune tolerance may become game-changers in treating ASCVD and preventing its downstream sequelae including heart attacks and strokes.