Following Spinal Cord Injury (SCI) the injured neurons are unable to regenerate as they face an inhibitory external environment and the lack of guidance cues for direct regrowth of severed axons. A component of the inhibitory extracellular environment is the glial scar. Chondroitinase ABC (ChABC) is an enzyme able to degrade the sugar chains of chondroitin sulfate proteoglycans (CSPGs), a major constituent of the glial scar, and thus allow for improvements in SCI functional repair. The mechanism underlying this repair remains unclear. Our group has previously reported that ChABC enhances the interaction of the extracellular serine protease, tissue plasminogen activator (tPA) and its downstream product, plasmin, with the extracellular matrix molecules of the glial scar in in vitro and ex vivo models of SCI. In my Dissertation, I tested the contribution of tPA/plasmin to ChABC promoted axonal repair using mice deficient in tPA (tPA KO), hypothesizing that tPA acts downstream of ChABC to promote axonal plasticity after SCI. I found that tPA is upregulated after a moderate contusion in wildtype (WT) mice, and that in the absence of the tPA/plasmin system, CSPG (NG2, Neurocan, and Phosphacan) degradation is reduced after ChABC treatment. In contrast to their genotypic equivalent WT cultures, tPA KO primary cortical neurons grown on ex vivo SCI homogenates show attenuated neurite outgrowth after ChABC treatment. Co-administration of ChABC and plasmin can rescue this phenotype. To test the hypothesis in vivo, I performed motor behavior assay and sensory anatomical tracings. A single high-dose bolus injection of ChABC allowed for significant sensory axon outgrowth and motor recovery in WT SCI mice but attenuated recovery in tPA KO mice. Furthermore, therapeutic co-administration of plasmin with ChABC enhanced the behavioral and axonal recovery in WT SCI mice over recovery due to the enzyme alone. Collectively, these findings suggest that after SCI, the tPA/plasmin system plays an important role in ChABC-mediated axonal plasticity and may provide new opportunities to enhance the enzyme's treatment efficacy.