Epidemiological studies clearly indicate that posttraumatic stress disorder (PTSD) is becoming a major health concern worldwide even if still poorly recognized and not well treated. PTSD commonly co-occurs with other psychiatric disorder, especially with major depression. However, the relationship between these disorders and the treatment of this complex clinical entity are only now being addressed in the specialized literature. Some authors argued that they are two distinct entities, whereas others defended the hypothesis that the high prevalence of this comorbidity may represent an artifact derived from the diagnostic criteria currently used. Regarding the treatment of PSTD comorbid with major depression, the available data from controlled studies are insufficient to point out for a specific approach, although some small trials reported the usefulness of combining selective serotonin reuptake inhibitors and cognitive therapy.