The p75 neurotrophin receptor (p75NTR) was originally identified as a low-affinity receptor for neurotrophins. Recent studies have revealed that p75NTR can promote cell death or survival and modulate neurite outgrowth depending on the operative ligands and co-receptors. Up-regulation and ligand activation of p75NTR have been shown to be involved in neuronal cell death in cultured cells and animal models of neurodegenerative diseases. The levels of proneurotrophins, which bind to p75NTR to promote neuronal death, have been found to be increased in postmortem brains of patients with Alzheimer's disease. Furthermore, there is some evidence for the involvement of this molecule in psychiatric diseases, such as depression and schizophrenia. Mice lacking p75NTR have been shown to have several alterations in central nervous system and cognitive function. Notably, recent progress in genome-based drug discovery has enabled the identification of peptides and non-peptide small molecules targeting p75NTR, which may be potentially beneficial in the treatment of neuropsychiatric diseases. In this review, we focus on recent findings on p75NTR as a therapeutic target for neuropsychiatric diseases.