Atherosclerosis has been studied in animals for almost a century, yet the events leading up to the rupture of an atherosclerotic plaque (the underlying cause of the majority of fatal thrombosis formation) have only been studied in the past decade, due in part to the development of a mouse model of spontaneous plaque rupture. Apolipoprotein E knockout mice, when fed a high-fat diet, consistently develop lesions in the brachiocephalic artery that rupture at a known time point. It is therefore now possible to observe the development of lesions to elucidate the mechanisms behind the rupture of plaques. Critics argue that the model does not replicate the appearance of human atherosclerotic plaque ruptures. The purpose of this review is to highlight the reasons why we should be looking to the apolipoprotein E knockout mouse to further our understanding of plaque rupture.