The role of p75 neurotrophin receptor (p75NTR) in mediating cell death is now well characterized, however, it is only recently that details of the death signaling pathway have become clearer. This review focuses on the importance of the juxtamembrane Chopper domain region of p75NTR in this process. Evidence supporting the involvement of K+ efflux, the apoptosome (caspase-9, apoptosis activating factor-1, APAF-1, and Bcl-xL), caspase-3, c-jun kinase, and p53 in the p75NTR cell death pathway is discussed and regulatory roles for the p75NTR ectodomain and death domain are proposed. The role of synaptic activity is also discussed, in particular the importance of neutrotransmitter-activated K+ channels acting as the gatekeepers of cell survival decisions during development and in neurodegenerative conditions.