ABSTRACTThe death domain (DD) is a globular protein motif with a signature feature of an all‐helical Greek‐key motif. It is a primary mediator of a variety of biological activities, including apoptosis, cell survival and cytoskeletal changes, which are related to many neurodegenerative diseases, neurotrauma, and cancers. DDs exist in a wide range of signalling proteins including p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. The specific signalling mediated by p75NTR in a given cell depends on the type of ligand engaging the extracellular domain and the recruitment of cytosolic interactors to the intracellular domain, especially the DD, of the receptor. In solution, the p75NTR‐DDs mainly form a symmetric non‐covalent homodimer. In response to extracellular signals, conformational changes in the p75NTR extracellular domain (ECD) propagate to the p75NTR‐DD through the disulfide‐bonded transmembrane domain (TMD) and destabilize the p75NTR‐DD homodimer, leading to protomer separation and exposure of binding sites on the DD surface. In this review, we focus on recent advances in the study of the structural mechanism of p75NTR‐DD signalling through recruitment of diverse intracellular interactors for the regulation and control of diverse functional outputs.