Atherosclerosis is a complex, progressive disease of the large systemic arteries. This multi-factorial disease is characterized by accumulation of lipids, cells and extracellular matrix in the vessel wall. The quest to unravel the molecular mechanisms leading to progression of human atherosclerotic plaques has lead to the development of a variety of animal models. Mice are easily amendable to transgenesis and multiple mutant and inbred strains have been generated in which potential regulators are manipulated and subsequently studied for effects on the development and progression of atherosclerosis. The scope of this review is to discuss the relevance, advantages and disadvantages of genetically-engineered mice to investigate mechanisms of plaque vulnerability. Features of human vulnerable lesions, such as large lipid-rich necrotic cores, active inflammation, matrix remodeling and signs of intraplaque hemorrhage are represented in mouse lesions. Here, we will discuss how atherosclerosis is modified by manipulations in apoptosis, lesional lipid metabolism, inflammatory pathways, matrix remodeling and thrombotic pathways in genetically-engineered mice, emphasizing the insights that have been gained from these studies for the control of plaque vulnerability.