The pathology of atherosclerotic lesions that develop in mouse models of atherosclerosis, such as those lacking apolipoprotein E or lacking the low density lipoprotein receptor, is very similar to that seen in human patients. Consequently, genetic approaches to studying atherosclerosis in these mouse models have produced a wealth of information relevant to the genetic factors and pathways that modify the early stages of atherosclerosis in humans. Despite these advances, the later stages of atherosclerosis in humans, including spontaneous plaque rupture and hemorrhage, have not been observed reliably in current mouse models. Increasing sophistication and use of genetic manipulations, however, has produced significant advances in modeling these processes. The use of genetic tools to examine the physiology, pathology, and cell biology of atherosclerosis will enhance elucidation of the pathogenesis of the disease and lead to the development of novel therapeutic strategies.