Root avulsion of the brachial plexus is a devastating injury that results in massive motoneuron death and paralysis of the corresponding muscle groups. Various approaches such as pharmaceutical applications and microsurgical interventions have been extensively studied to restore the loss of injured motoneurons and recover function. However, the treatment for brachial plexus injury is still a challenging problem. The challenge that lies in brachial plexus injury treatment is that motoneuron death in the lesioned segments is relatively high and little is known about how inhibitory signals or lack of appropriate guidance molecules influences regeneration. This chapter summarizes the anatomical structure of the brachial plexus, the experimental models of brachial plexus avulsion, neuronal and glial responses to avulsion injury, and cellular and molecular profiles in the avulsed spinal cord at various ages and in various species. This chapter also summarizes a number of potential strategies for the treatment of brachial plexus avulsion, including microsurgical interventions using peripheral nerve graft or ventral root reimplantation; the use of small molecules, trophic factors, or small interfering RNA to promote motoneuron survival and regeneration; the application of inhibitors of the degeneration pathway; cell-based therapies; and, last, combined therapies for brachial plexus avulsion. We believe that a combination of multiple treatments may be necessary to acquire the most beneficial effects in treating the devastating injury characterized by motoneuron loss.