Stroke, traumatic brain injury (TBI), and spinal cord injury (SCI) cause irreversible damage to the nervous system. Although these are neurological disorders, pathology and loss of function also occur outside the nervous system and are often not easily explained by paralysis or impaired neural function. Emerging data indicate that much of the pathological sequelae that accompanies CNS trauma has characteristics of a self-directed immunological disease. Here, we outline those data, describing basic mechanisms of B cell activation and autoantibody synthesis after CNS injury. A summary of the anti-CNS autoantibodies that have been identified in humans and animals is provided along with a discussion of how autoantibodies may affect survival of neuronal and non-neuronal tissues and whether autoimmune reactions are feasible therapeutic targets after CNS trauma.