Axons can represent the majority of a neuron's volume and are energetically demanding. Specialized glia ensheathe axons to insulate them and are believed to support axon function and maintenance throughout life. The morphology of axon-associated glia is complex and requires massive growth during development. Glial cells must search for and identify the proper axonal targets, sort them from other axons, and ultimately fully ensheathe them. Despite their importance, little is known about how glia ensheathe axons, what glia do to support neurons, and even less is known about how those functions are regulated throughout the life of an organism. Understanding the mechanisms involved in coordinating this complex process is critical as improper ensheathment can impede the ability of glia to support axons. Human diseases such as multiple sclerosis (MS) or Charcot-Marie-Tooth disease (CMT) are characterized by loss of glia that ensheathe axons resulting in functional impairment and progressive degeneration of neurons. In this dissertation I sought to provide new insights into how glia support neurons and in doing so, identified several genes encoding secreted and transmembrane proteins that are required in glia for long-term axon survival in vivo.