The low-density lipoprotein (LDL) receptor is the prototype of a classical endocytosis receptor that mediates the uptake of extracellular ligands. Other members of the LDL receptor gene family, on the other hand, have been shown to regulate intracellular signalling cascades. Among these are the LDL receptor-related protein 1, LRP1, a promiscuous and ubiquitously expressed receptor which is critically involved in a multitude of diverse physiological processes; the Reelin receptors ApoER2 and VLDL receptor, which participate in neuronal development; and megalin, a multifunctional receptor expressed in various epithelia. In this review, we focus on recent developments that highlight similarities and differences between these related receptors and their biological function, and discuss open questions as to the underlying molecular mechanisms.