Epidemiological evidence indicates that exposure to combustion-derived particles is linked to an increased risk of cardiovascular disease. Despite this strong association, there remains a lack of data that can be used to identify the molecular mechanisms through which exposure to particulate matter (PM) leads to adverse cardiovascular events. The biological complexity of the responses generated by exposure to PM is compounded by the inherent multidimensional nature of the chemical mixtures associated with PM emitted from a range of sources, including diesel and gasoline exhausts, cigarette smoke, and ambient particles. The current challenges in this field of toxicology include the development and adoption of standardized in vitro and in vivo methods for testing multiple types of PM as individual entities or as mixtures. In this chapter, we focused on studies that have been published on the effects of combustion-derived PM in the ApoE-deficient mouse, a model of atherosclerosis that has proven to be a powerful in vivo surrogate for vascular disease in humans. A number of studies have been conducted in which the effects of diesel and gasoline exhausts, cigarette smoke, and concentrated ambient particles have been investigated, however, the exposure times, routes of PM delivery, and end points used in those studies have varied widely, making it challenging to compare the results of the studies. Despite these limitations, a few key findings on the development of vascular lesions in ApoE −/− mice can consistently be extracted from the published data. Future efforts should be aimed at systematizing the experimental designs and functional and molecular end points in studies using ApoE −/− mice so that the effects of different sizes and types of PM can be compared reliably. Functional end points and molecular data generated using ‘omics’ approaches, in which the transcriptome, lipidome, and proteome of ApoE −/− mice exposed to a diverse range of PM sources are examined, will be invaluable components in a systems biology approach to achieving a full understanding of the underlying biology of exposure to combustion-derived PM.