In contrast to the limited repair observed in the mammalian central nervous system (CNS), injured neurons in the leech reliably regenerate synapses and restore function with remarkable accuracy at the level of individual neurons. New and recent results reveal important roles for microglial cells and extracellular matrix components, including laminin, in repair. Tissue culture experiments have permitted isolation of neurons and manipulation of their environment, providing insights into the influence of substrate, electrical activity, and other cells, including microglia, on axon growth and synapse formation. The results account for distinctive features of successful repair in the adult leech, where axonal sprouting and target selection can be influenced by unequal competition between neurons. Differences between the formation of connections during embryonic development and repair in the adult include dissimilarities in the roles of glia and microglia in adults and embryos, suggesting that axon growth during regeneration in the CNS is not simply a recapitulation of processes observed during embryonic development. It may be possible in the future to improve mammalian CNS regeneration by recruiting cells whose counterparts in the leech have been identified as instrumental in repair.