The LDL receptor (LDLR) family is comprised of several multifunctional cell surface proteins that bind and endocytose ligands with diverse biological functions. One ligand common to all LDLR family members is apolipoprotein E (apoE), a lipid transport protein that also plays a central role in the pathogenesis of neurodegeneration in Alzheimer's disease. This review discusses the role of apoE and its receptors in the central nervous system and, in particular, the signaling mechanisms by which two members of the LDLR gene family, apoE receptor-2 and VLDL receptor, control brain development, normal neuronal positioning, and neurotransmission in the adult brain.