Many neurons depend for their survival on retrograde signals to their cell bodies generated by nerve growth factor (NGF) or other neurotrophins at their axon terminals. Apoptosis resulting from the loss of retrograde NGF signaling contributes to the elimination of excess and misconnected neurons during development and to the death of neurons during the course of neurodegenerative diseases. Possible mechanisms of retrograde signaling include (1) retrograde transport of signaling endosomes, carrying NGF bound to activated TrkA, (2) retrograde transport of signaling molecules downstream of TrkA, and (3) retrograde propagation of a phosphorylation signal without transport of signaling molecules. Evidence is also described, which indicates that two or more retrograde signaling mechanisms exist to regulate neuronal survival, including recent evidence that withdrawal of NGF from distal axons produces a retrograde apoptotic signal, which is transported to the cell bodies, where it initiates the apoptotic program, leading to the death of the neuron.