The choice of pharmacologic treatment for cognitive, behavioral, or affective disorders following TBI depends upon an accurate diagnosis of the underlying disorder responsible for the clinical picture presented. However there are a myriad of possible causes for each sign or symptom, and often several contributing factors. A differential diagnostic approach is presented that structures the search for etiology into several categories: preinjury diagnosis, neuropsychological disorders, sensorimotor disorder, medical disorders, adverse effects of medications, reactive mood and anxiety disorders, and sleep disorders.