Experimental approaches to understand the pathophysiology of atherosclerosis and thrombosis involve the combination of both cellular and animal approaches. Animals have been instrumental in biomedical research in order to provide a better understanding on the mechanisms that have already been outlined in in vitro studies. Atherosclerosis studies were firstly carried out in rodents using diet-induced atherosclerosis approaches. However, these diets were un-physiological and the developed lesions were often limited in size, composition, and location largely differing from humans. During the last years, with the advent of molecular genetics and genetic manipulation techniques, the development of gene-engineered animals has allowed an explosion in the number of models resulting in a tremendous progress in the understanding of both atherosclerosis and thrombosis. However, direct translation from rodents to humans has to be taken with caution because of the well-reported species-related differences. Although there is no known animal model for human disease, large animal models have demonstrated better suitability for translation to humans. For instance swine, a species that spontaneously develops atherosclerosis and thrombosis, are more closely mimics of the macrovascular-related thrombotic complications found in humans. This book chapter provides an in depth overview of the currently available small and large animal modelsof atherosclerosis and thrombosis and examinestheir applicability for translational research purposes as well as highlights species-related differences with humans.