Post-traumatic stress disorder (PTSD) is a complex and challenging condition to treat. Researchers and clinicians have developed a growing interest in the psychological and neurobiological underpinnings of PTSD. Psychosocial treatment and pharmacotherapy have been shown to be effective in all three symptom clusters of PTSD: reexperiencing, avoidance/numbing, and hyperarousal. Research on the treatment of PTSD has focused on psychosocial treatments as well as pharmacotherapy, Both have shown clinical efficacy. This chapter provides the clinician with an overview and guidance in the use of medication for patients with PTSD. Psychotropic agents might theoretically facilitate the normal recovery process that takes place after a traumatic event or might mitigate the neurobiological processes that precede the development of chronic PTSD. Although psychosocial therapies are assumed to modulate the neurobiology of PTSD, the existence of neurobiological alterations in PTSD is also a logical rationale for the use of psychotropic agents. The majority of patients with PTSD suffer from one or more comorbid psychiatric disorders.