Mood disturbances are common sequelae of traumatic brain injury (TBI), but the scientific database for such disorders is very limited in descriptive, prognostic, and treatment data. Post-TBI symptoms often cross diagnostic boundaries and include cognitive loss, amotivation, psychosis, mood, changes, or other domains. The treating physician must be mindful that clear diagnostic boundaries may not exist.Premorbid level of functioning commonly affects post-TBI level of functioning. When setting treatment goals, this must be considered. Patients who had lower levels of psychosocial functioning before the injury may not fare as well afterwards.Treatment of post-TBI mood symptoms should proceed after a full diagnostic work-up including imaging and electroencephalographic (EEG) studies, neuropsychologic testing, and physical and laboratory examinations. Once the diagnostic picture is established, treatment should then proceed with a multidisciplinary team (physician, social worker, neuropsychologist, and others). For the medications, consider both target symptoms and side effects; start medications with low doses and raise slowly, give full therapeutic trials before switching or adding second agents, avoid benzodiazepines if possible, limit anticholinergic or antidopaminergic agents, and avoid providing large quantities of lethal medications.When starting medications for the treatment of mood disorders following TBI, several general principles of treatment in this population should be considered, including: balancing treatment of target symptoms with the potential for adverse effects; making use of side effects to treat comorbid problems when present (ie, relatively antidepressant for depression and marked insomnia); using a “start low, go slow” approach; continuing dose escalation to full therapeutic levels (ie, completing therapeutic trials) before switching or adding augmenting agents; avoiding agents with predictable and functionally important adverse effects (ie, benzodiazepines, strongly anticholinergic or antidopaminergic agents); and avoiding prescription of large and potentially lethal quantities of medications.