The neurotrophins mediate diverse actions in the developing peripheral and central nervous systems. They are initially synthesized as precursor forms, or proneurotrophins, that are cleaved to release C-terminal mature forms that bind to Trk receptor tyrosine kinases to enhance synaptic plasticity and neuronal survival. Recent studies suggest that proneurotrophins are not inactive precursors, but signaling proteins that can activate the p75 receptor to mediate diverse responses. Proneurotrophins can activate a heteromeric receptor complex of p75 and sortilin to initiate cell death, or bind to p75 in hippocampal neurons to enhance long term depression. Thus, neurotrophin actions are regulated by the form of the neurotrophin (pro- or mature) secreted by cells, by extracellular proteolytic cleavage of proneurotrophins to generate mature forms, and by the expression of neurotrophin receptors Trk, or p75 and sortilin, that are selectively activated by mature or proneurotrophins, respectively. Here, recent studies are reviewed that reveal that pro- and mature neurotrophins have distinct and sometimes opposing actions in regulating cell death and survival in development and in pathophysiologic states, in regulating neurotrophin secretion, and in modulating synaptic plasticity.