The formation of the nervous system during embryonic development is controlled by a complex network of signaling pathways which ensure proper migration and targeting of neuronal projections. Likewise, the function of the adult nervous system relies on complex dynamic interactions between the presynaptic and postsynaptic terminals. Here, we review recent advances in understanding the molecular pathways underlying these seemingly distinct processes. These studies reveal that the conserved E3 ubiquitin ligase PHR (PAM, highwire Rpm-1) controls a regulatory protein degradation pathway essential both for axonal targeting during embryonic development as well as for the proper formation and function of neuron muscular junctions (NMJ).