Nerve injuries induce severe disability and suffering for patients. Profound alterations in nerve trunks, neurons, and the central nervous system are induced rapidly after injury. This includes activation of intracellular signal transduction mechanisms aiming at the transfer of the cells into a regenerative state through the induction of the appropriate gene programs. The understanding of the neurobiological mechanisms that occur after injury can be used to design modern strategies for reconstruction after nerve injuries. Signal transduction mechanisms for instance may be targets for pharmacological intervention to stimulate nerve regeneration. Nerve injuries, particularly where there is a defect between the severed nerve trunks like in brachial plexus lesions, remain a challenge for the surgeon. Reconstruction of nerve injuries with a defect requires utilization of graft material, which can be of various designs. Application of autologous nerve grafts and use of nerve transfers are the most common clinical solutions to overcome problems with nerve defects. In this chapter we discuss the future perspective of nerve reconstruction with focus on signal transduction mechanisms and new avenues to bridge nerve defects using nanomodified graft surfaces.