Spine cord injury (SCI) leads to devastating functional loss below the level of injury. Partially explained by the presence of a non-permissive environment, the injured spinal cord does not mount adequate regeneration to re-establish functional connections. Therefore, it is important to identify the cellular and molecular factors and their interactions that affect axonal regeneration within the changed environment. This review will discuss the current understanding of the neuronal and glial factors and the extracellular matrix in the spinal cord that inhibit axonal growth, and it will summarize some major approaches for facilitation of regeneration. The strategies are classified into the following categories: penetration of the blood-brain barrier; modulation of caspase activity to reduce apoptosis; stem cells and tissue implantation; administration of neurotrophic factors, including viral vector-mediated delivery; and modulation of the extracellular matrix. Although recent studies on genomic regulation and apoptosis have identified particularly important molecular targets, more is necessary to achieve long-term regeneration. A combination of the approaches targeting various aspects in the regenerating environment would be more effective than a single strategy. Overall, insights arising from the experimental results may eventually lead to better therapeutic intervention so as to lessen the functional disability and enhance the quality of life in patients with SCI.