The formation of myelin is dependent on a reciprocal and intimate relationship between neurons and the myelin-forming glia. Recently, the neurotrophin family of growth factors has been shown to regulate the complex cell–cell interactions that control myelination. Neurotrophins and their receptors influence myelin formation via two distinct mechanisms, either by acting on the neurons, changing the axonal signals that control myelination, or by acting directly on the myelin-forming glia. In this review, we will discuss research highlighting the ability of neurotrophins to both promote and inhibit the myelination process. As reflected in the work presented here, these effects are dependent on a delicate balance of which neurotrophins are expressed, and what receptors are activated. Additionally, we examine an emerging model in which the growth factors that promote the early survival and differentiation of particular sets of neurons later play important roles as key regulators in glial development. Characterizing the temporal expression and the cellular targets of neurotrophins, both during development and after injury, represents a pivotal step in developing a greater understanding of the myelination process, contributing to the development of effective treatments for demyelinating conditions. We conclude this review by discussing the potential for neurotrophins as therapeutics in the quest for remyelination.