Reciprocal interactions between differentiating glial cells and neurons define the course of nervous system development even before the point at which these two cell types become definitively recognizable. Glial cells control the survival of associated neurons in both Drosophila and mammals, but this control is dependent on the prior neuronal triggering of glial cell fate commitment and trophic factor expression. In mammals, the growth factor neuregulin-1 and its receptors of the ErbB family play crucial roles in both events. Similarly, early differentiating neurons and their associated glia rely on reciprocal signaling to establish the basic axon scaffolds from which neuronal connections evolve. The importance of this interactive signaling is illustrated by the action of glial transcription factors and of glial axon guidance cues such as netrin and slit, which together regulate the commissural crossing of pioneer axons at the neural midline. In these and related events, the defining principle is one of mutually reinforced and mutually dependent signaling that occurs in a network of developing neurons and glia.