In the central nervous system (CNS) of mammals axonal regeneration is limited by two main factors: first, the low intrinsic regenerative potential of adult CNS neurons and second, inhibitory influences of the glial and extracellular environment. Myelin-associated inhibitors of neurite growth as well as some properties of so called "reactive astrocytes" contribute to the non-permissive of CNS tissue for axonal growth. In contrast, the peripheral nervous system (PNS) environment is supportive of regeneration because Schwann cells provide suitable substrates for regrowing axons. Purified PNS myelin, however, inhibits growth of PNS and CNS axons to a similar extent as does CNS myelin. The molecular basis of glial substrate properties has been studied intensively in the recent years and a large number of molecules have been recognized which might play a role in the regulation of axonal growth. Although the exact mechanisms are still not fully understood, accumulating data shed light on the complex interactions between neurons and glia that are required to establish, maintain, and regenerate axonal connections in the nervous system. In the following chapter we review the role of glial cells in the CNS and PNS during processes of de- and regeneration with respect to our own work.