Individual axons of central neurons innervate a large number of distinct postsynaptic targets belonging to divergent functional categories such as glutamatergic principal cells and inhibitory interneurons. While each bouton along a common axon should experience the same activity pattern in response to action potential firing within the parent presynaptic neuron, accumulating evidence suggests that neighboring boutons contacting functionally distinct postsynaptic targets regulate their release properties independently, despite being separated by only a few microns. This target-cell specific autonomy of presynaptic function can greatly expand the computational prowess of central axons to allow for precise coordination of large neuronal ensembles within a given circuit. An excellent example of target-cell specific presynaptic mechanisms occurs in the CA3 hippocampus where mossy fiber axons of dentate gyrus granule cells target both principal cells and local circuit inhibitory interneurons via both anatomically and functionally specialized terminals. Of particular interest, mechanisms of both short- and long-term plasticity remain autonomous at these divergent release sites due to an anatomical and biochemical segregation of discrete molecular signaling cascades. Here we review roughly a decades worth of research on the MF-CA3 pathway to showcase the target-cell dependence of presynaptically expressed NMDA receptor-independent synaptic plasticity.