The application of methods to create transgenic mice in which a gene of interest is either overexpressed or genetically inactivated has provided us with an ever-growing number of animal models to study complex physiological processes in vivo. Analysis of these mouse models has increased our knowledge about basic mechanisms that control biological systems and the pathological processes in human genetic disorders. This review focuses on the analysis of mouse models in which individual components of the hepatic clearance pathway for plasma lipoproteins have been inactivated. These studies have demonstrated that two hepatic lipoprotein receptors, the low-density lipoprotein receptor and the low-density lipoprotein receptor-related protein operate jointly in the uptake of dietary lipoproteins from the circulation. These findings have important implications for our understanding of pathophysiological processes resulting in hyperlipoproteinemia and atherosclerosis in patients.