Throughout the history of atherosclerosis research we have sought animal models of the disease process that exhibit high frequencies of the features that make human plaque a clinical risk: plaque rupture, mural thrombosis, and intra-plaque hemorrhage. This type of model is needed to determine the mechanisms by which plaques rupture and to design and test therapeutic interventions for stabilizing plaques. Studies of domestic and exotic animals have shown that most species will spontaneously develop fatty streaks and in some cases atheromatous lesions with sufficient time, but that rupture and thrombosis is exceedingly rare. Even with addition of fat and cholesterol to the diet, lesion development is accelerated but does not increase the frequency with which plaques rupture in most animal models. However, recently we have observed high frequencies of intra-plaque hemorrhage in the innominate/brachiocephalic arteries of older, chow-fed, hyperlipidemic, apolipoprotein E-deficient mice, and high frequencies of plaque rupture with mural thrombus in younger apolipoprotein E-deficient mice fed a high-fat diet. This suggests that plaque rupture and secondary thrombosis are frequent and reproducible occurrences at specific sites in apolipoprotein E-deficient mice, and that the timing and pathobiology of the ruptures are influenced by lipid status in this murine model.