The multifaceted functions of apolipoprotein E (apoE), including its role in lipid transport and signal transduction in cell regulation, are mediated via its interaction with heparan sulfate proteoglycans and proteins in the low-density lipoprotein receptor (LDLR) gene family on the plasma cell membrane. The LDLR family proteins are cell surface receptors that share similar structural characteristics, and each receptor has many different ligands. Ligand interaction with LDLR family proteins results in their endocytosis and/or triggers signal transduction pathways via interactions of specific adaptor proteins with functional motifs in the cytoplasmic tail of the receptor, which in turn is dependent on the specific ligand bound to the receptor, the cell type, and the environment involved. Ligands bound to the receptor extracellular domain are internalized in endosomes where ligand-receptor uncoupling occurs, and the receptor is recycled back to the cell surface. This chapter discusses the physiological functions of three major LDLR family proteins, namely, LRP1, apoER2, and VLDLR, and how they participate in a cell type-dependent manner to impact cardiovascular, metabolic, and neurological health and disease pathogenesis. The mechanisms underlying the protective effects of apoE3 on pathogenesis as well as how apoE4 contributes directly to disease pathogenesis will also be discussed.