Axon regeneration and neuronal tissue repair varies across animal lineages as well as in the mammalian central and peripheral nervous systems. While the peripheral nervous system retains the ability to self-repair, the majority of axons in the adult mammalian central nervous system (CNS) fail to reactivate intrinsic growth programs after injury. Recent findings, however, suggest that long-distance axon regeneration, neuronal circuit assembly and recovery of functions in the adult mammalian CNS are possible. Here, we discuss our current knowledge of the cell signaling pathways and networks controlling axon regeneration. In addition, we outline a number of combinatorial strategies that include among others microtubule-based treatments to foster regeneration and functional connectivity after CNS trauma.