Complete axon regeneration after trauma or disease is largely unsuccessful in the central nervous system. With the fast developing advances in tissue engineering and biomaterials, many investigations have identified promising approaches for guiding axonal extension. This review highlights a variety of these approaches and describes the biomaterial properties and signaling mechanisms involved in the fabrication of optimal guidance platforms. The vast majority of axonal regeneration approaches limit themselves to observe how axons elongate and migrate in response to signaling molecules presented on the substrate materials, or more recently, in response to different chemical and mechanical substrate properties. Many of these studies are encouraging in the hope of regenerating axons after disease or injury; however, numerous barriers remain. Here we illustrate the need to optimize a permissive heterogeneous environment for axon elongation using tissue engineering approaches and a thorough understanding of the mechanical properties of the substrate, mechanotaxis, and both attractive and repulsive signaling mechanisms.