Despite the number of animal models of atherosclerosis, a major limitation in research on mechanisms of plaque rupture is the lack of appropriate atherosclerotic mouse models where lesions develop and progress to a vulnerable and thus rupture-prone phenotype that is typically observed in humans. Most animal models of atherosclerosis typically represent a few but not the full combination of the characteristics seen in human unstable/ruptured plaques. Such characteristics most importantly include a thin and ruptured fibrous cap, plaque inflammation, neovascularization within the plaque (vasa vasorum), plaque hemorrhage, and intravascular (often occlusive) thrombus formation. Ideally, an animal model of plaque instability/rupture would respond to current pharmacological interventions known to reduce the risk of plaque rupture, such as statins. Here we describe a mouse model of plaque instability/rupture that is based on the surgical introduction of a tandem stenosis in the carotid artery. This model results in the formation of unstable atherosclerotic plaques that reflect human plaque pathology. It will allow to further understanding of plaque instability/rupture, to identify the participating factors such as specific proteins, genes and microRNAs, and to develop imaging methods towards the detection of vulnerable, rupture-prone atherosclerotic plaques.