Neurotrophins are initially synthesized as larger precursors (proneurotrophins), which undergo proteolytic cleavage to yield mature forms. Although the functions of the mature neurotrophins have been well established during neural development and in the adult nervous system, roles for the proneurotrophins in developmental and injury‐induced cell death, as well as in synaptic plasticity, have only recently been appreciated. Interestingly, both mature neurotrophins and proneurotrophins utilize dual‐receptor complexes to mediate their actions. The mature neurotrophin coreceptors consist of the Trk receptor tyrosine kinases and p75^NTR, wherein Trk transduces survival and differentiative signaling, and p75^NTR modulates the affinity and selectivity of Trk activation. On the other hand, proneurotrophins engage p75^NTR and the structurally distinct coreceptor sortilin, to initiate p75^NTR‐dependent signal transduction cascade. Although the specificity of mature neurotrophins vs. proneurotrophins actions is due in part to the formation of distinct coreceptor complexes, a number of recent studies highlight how different p75^NTR‐mediated cellular actions are modulated. Here, we review emerging evidence for a novel transmembrane mechanism for ligand‐specific p75^NTR activation and several mechanisms by which p75^NTR‐dependent apoptotic and nonapoptotic responses can be selective activated. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 2010