Glycosphingolipids (GSL) are complex, sugar-containing lipids that are transported in plasma on lipoproteins, particularly low density (beta) lipoproteins (LDL). LDL are taken up and metabolized by cells through a LDL receptor-mediated pathway. Cells from receptor-negative familial hypercholesterolemic (FH) homozygotes lack a functional LDL receptor and the cellular uptake of LDL occurs through a LDL receptor-independent pathway. We have studied the relation between LDL and GSL metabolism using an in vitro model of cultured human fibroblasts and an in vivo model of renal tubular cells shed in the urine. Using biochemical, morphological, and immunocytological techniques, we have demonstrated that LDL taken up through the LDL receptor-independent pathway results in the accumulation of GSL in cells in vitro and in vivo. The storage of GSL is localized to intracytoplasmic vesicles and such storage can be modulated by changing the concentration of LDL in the culture medium or in plasma. The possible effect of LDL on certain steps in the intracellular metabolism of GSL in normal and receptor-negative-homozygous FH cells is reviewed.