The paralysis of an acute spinal cord injury (SCI) remains a catastrophic condition for which there are currently no effective treatments. While the diagnosis of acute traumatic SCI is typically quite easy to make, distinguishing the exact degree of severity and prognosticating the extent of neurologic recovery are challenging. Functional neurologic measures are currently used to stratify injury severity and predict neurologic outcome. However, these measures are often impossible to determine in acutely injured patients. Additionally, for patients deemed to be of a specific injury severity, the variability in spontaneous neurologic recovery is high. Both of these issues severely impair the ability to perform clinical trials in novel therapies for SCI. Biomarkers that could more precisely define the severity of injury and better predict neurologic outcome would be extremely valuable. Furthermore, biological surrogate outcomes measures would be very useful in small preliminary clinical trials of novel therapies if they could inform decisions around the therapeutic regimen for subsequent larger clinical trials. This review highlights our ongoing work in establishing biomarkers for SCI using cerebrospinal fluid samples from acutely injured patients.