Abstract: Neurotrophins have been recognized for decades for their beneficial effects on growth, survival, and maintenance in the central nervous system, all of which suggest potential therapeutic utility. Although understanding and harnessing the activity of neurotrophins has proven difficult, the past several years have seen significant strides in the development of deliverable therapies that modulate neurotrophin activity (Shen et al., 2019; Yang et al., 2020; Xie et al., 2021). These recent studies have primarily focused on the multifunctional p75 neurotrophin receptor (p75NTR) which is upregulated in central nervous system disease and injury, thus offering a unique target for intervention. Animal studies focusing on neurodegenerative diseases, infection and injury have all illustrated the potential benefit of p75NTR modulation, such as prevention of neural damage via restoration of calcium homeostasis, facilitation of pro-survival signaling, and reduction of inflammation. In addition, new studies have revealed important interactions of p75NTR with microtubule-associated protein, Tau, relevant to Alzheimer’s disease (AD) pathogenesis, tauopathies, injury, and infection. Importantly, these investigational therapies have also been shown to be effectively deliverable as well as tolerable, with few side effects in animal models. Although the actions of p75NTR are complex and studies have only begun to reveal their potential utility, these new developments have paved the way for clinical trials of focused, modulatory interventions that have the potential to be broadly applicable in the treatment and prevention of central nervous system disease.