Optic nerves, like other CNS tracts, consist of axons closely apposed across narrow extracellular clefts to the cell bodies and processes of glial cells. Despite the anatomical simplicity of these pathways and the absence of synapses, a surprising range of interactions occurs between axons and glial cells mediated by changes in the chemical composition of the extracellular fluid produced by glial or neuronal stimulation. Some of the interactions are relatively brief, resulting from alterations in extracellular ions such as K+ or H+, or alterations of small molecules like glutamate or ATP. Other interactions involve much longer time periods and presumably larger signaling molecules, like peptides or proteins. These play a role not only in the development of axonal pathways but also in the processes of degeneration and regeneration that follow brain injury or disease.