Receptor-mediated endocytosis is the process whereby binding of a ligand to a cell-surface receptor is followed by internalization of the receptor-ligand complex. After reaching an acidic intracellular endosomal compartment, receptors and ligands are sorted along different pathways for delivery to lysosomes, transport across the cell, or return to the cell surface. Since the first description of receptor-mediated endocytosis in 1974, more than 50 ligands have been found to use receptors to gain access to the interior of the cell, and more than 15 receptors have been purified and sequenced. However, as Virginia Shepherd describes, there are still many unanswered questions concerning sorting signals involved in receptor-ligand routing and the proposed functions of receptor-mediated endocytosis.