Transgenic and knockout mice have been instrumental in delineating the role of apolipoprotein (apo) E in lipoprotein metabolism and atherosclerosis. The severe hypercholesterolemia and premature atherosclerosis of the apoE knockout mouse have been the starting point from which various physiologic processes have been identified in which apoE plays a critical role. These processes include 1) very low density lipoprotein (VLDL) triglyceride production; 2) lipoprotein lipase mediated triglyceride lipolysis; 3) VLDL remnant clearance and intracellular processing; and 4) the efflux of cellular cholesterol. In this review we will discuss the recent insight in the role of apoE in these processes, which has been obtained using a variety of in vivo and in vitro approaches to modify apoE expression and function.