The neurotrophins, a class of four related growth factors, utilize a dual receptor system consisting of Trk receptor tyrosine kinases and the structurally unrelated p75(NTR) to modulate diverse and sometimes opposing biological actions. The identification of novel ligands for p75(NTR), unconventional mechanisms for Trk activation and unique signaling intermediates further underscores the complex nature of neurotrophin: receptor interactions, as well as their functions within and outside of the nervous systems. This review summarizes recent surprises of how ligand-receptor pairing may affect diverse developmental events, regulate response to injury and extend their influence on memory and learning.