Neurotrophins were originally identified as target-derived factors that regulate the survival and differentiation of innervating neurons. However, neurotrophins can also be released by presynaptic cells to stimulate postsynaptic neurons. Recent studies indicate that differences exist between the signaling pathways activated by neurotrophin stimulation of nerve terminals (retrograde signaling) and neurotrophin stimulation of cell bodies. Retrograde signaling relies on the formation of signaling endosomes, vesicles containing activated Trk receptors and their ligands. Signaling endosomes travel from the nerve terminals to remote cell bodies, where they selectively activate a novel MAP kinase, Erk5, as well as PI3 kinase, and thereby stimulate neuronal survival. The differences in the signaling pathways activated by neurotrophins, which depends on the location of stimulation, provide a mechanism by which neurons can interpret the 'where' as well as the 'what' of growth factor stimulation.