Studies showing that neurotrophin binding to p75^NTR can promote cell survival in the absence of Trk (tropomyosin-related kinase) receptors, together with recent structural data indicating that NGF may bind to p75^NTR in a monovalent manner, raise the possibility that small molecule p75^NTR ligands that positively regulate survival might be found. A pharmacophore designed to capture selected structural and physical chemical features of a neurotrophin domain known to interact with p75^NTR was applied to in silico screening of small molecule libraries. Small, nonpeptide, monomeric compounds were identified that interact with p75^NTR. In cells showing trophic responses to neurotrophins, the compounds promoted survival signaling through p75^NTR-dependent mechanisms. In cells susceptible to proneurotrophin-induced death, compounds did not induce apoptosis but inhibited proneurotrophin-mediated death. These studies identify a unique range of p75^NTR behaviors that can result from isolated receptor liganding and establish several novel therapeutic leads.