The heparan sulfate proteoglycan (HSPG)/low density lipoprotein (LDL) receptor-related protein (LRP) pathway plays a critical role in apolipoprotein (apo) E-containing lipoprotein metabolism in hepatocytes and other cells, including neurons. In this review, it will be shown that the HSPG sequestration step (i.e., the recruitment and trapping of remnant lipoproteins in the space of Disse in the liver) is an important component of remnant metabolism mediated by apo-E. In vitro studies indicate that the apo-E-containing lipoproteins must first interact with HSPG; only then does the LRP mediate lipoprotein uptake. The differential interaction of apo-EIII and the various mutant forms of apo-E with this pathway before internalization appears to be one factor that modulates the expression of recessive versus dominant type III hyperlipoproteinemia. Furthermore, it is now apparent that the HSPG/LRP pathway is involved in the delivery of apo-E to neurons, where apo-E alters neurite growth and cytoskeletal activity in these cells. Specifically, apo-EIV, which has been associated with the pathogenesis of Alzheimer's disease, inhibits neurite extension and microtubule formation subsequent to the interaction of apo-EIV with the HSPG/LRP pathway.