Loss of function after spinal cord injury (SCI) results from the primary injury that causes interruption of axonal tracts, neuronal and glial cell death, and the secondary injury in which inflammation drives lesion expansion, and further loss of gray and white matter. There are two main therapeutic strategies for the treatment of SCI: pro -reparative sprouting strategies that aim to promote functional recovery through enhancing the plasticity of spared axons and neuroprotection/anti-inflammatory strategies that aim to decrease secondary injury. Chondroitin sulfate proteoglycans (CSPGs) are matrix molecules that are major constituents of the glial scar at the SCI epicenter and of perineuronal nets found throughout the central nervous system. In this review, we summarize the wealth of literature describing the application of anti-CSPG strategies that target either CSPG synthesis or degradation or signalling after SCI. The weight of the evidence suggests that the balance between neuroprotection and neuroplasticity achieved by any one anti-CSPG strategy depends on the when and the where of its application.