LDL Receptor-related Protein (LRP1) is an endocytic receptor for as many as 100 distinct ligands including apolipoprotein E-containing lipoproteins, proteases and their inhibitors, growth factors, extracellular matrix proteins, and intracellular proteins released by injured cells. LRP1 also binds non-pathogenic cellular prion protein, which is released from cells in soluble form or carried by endosomes and other extracellular vesicles (EVs). In many cells, including macrophages, neurons, and Schwann cells, ligand-binding to LRP1 regulates cell-signaling. These cell-signaling events have profound effects on cell physiology. In neurons, LRP1-initiated cell-signaling promotes neurite outgrowth. In Schwann cells, LRP1-activated cell-signaling promotes cell-survival and in macrophages, LRP1-activated cell-signaling opposes the activity of Toll-like Receptors in innate immunity. The activity of LRP1 in cell-signaling does not reflect LRP1 alone but instead, a multiprotein receptor assembly. The NMDA Receptor is essential for activation of cell-signaling by LRP1 ligands. Other receptors that may participate include membrane-anchored cellular prion protein, Trk receptors, and p75NTR. The activity of LRP1 as a cell-signaling receptor for EV-associated cellular prion protein indicates that LRP1 responds not only to soluble proteins but also to plasma membrane-anchored ligands. Understanding the scope of activity of LRP1 and its partner receptor, the NMDA-R, in cell-signaling and in the regulation of cell physiology is a major goal.