Traumatic brain injury (TBI) is a major cause of death and disability in the United States. While there are no pharmacotherapeutic options currently available for attenuating the neurologic injury cascade after TBI, numerous pharmacologic issues are encountered in these critically ill patients. Adequate fluid resuscitation, reversal of coagulopathy, maintenance of cerebral perfusion, and treatment of intracranial hypertension are common interventions early in the treatment of TBI. Other deleterious complications such as venous thromboembolism, extremes in glucose concentrations, and stress-related mucosal disease should be anticipated and avoided. Early provision of nutrition and prevention of drug or alcohol withdrawal are also cornerstones of routine care in TBI patients. Prevention of infections and seizures may also be helpful. Clinicians caring for TBI patients should be familiar with the pharmacologic issues typical of this vulnerable population in order to develop optimal strategies of care to anticipate and prevent common complications.