Fatigue is a common complaint in the community and medical care settings. Different studies show a high comorbidity between fatigue and depressive disorder. Furthermore, fatigue is an important somatic symptom of depressive disorder and one of the main depressive presentations in primary-care medicine. Fatigue shows a slow response to antidepressant treatment and psychotherapy. Improved work performance is strongly correlated to improvement in energy. However, the assessment and treatment of fatigue in depressive disorder remains understudied. Different definitions of fatigue in depressive disorder are applied in DSM-IV and ICD-10, and depression rating scales all show a different coverage of this core depressive symptom, thereby hampering scientific research. Serotonin, norepinephrine, dopamine and histamine mediate symptoms of fatigue in depressive disorder. Although few data address the effect of antidepressants or augmentation strategies on fatigue-related symptoms, there is a pharmacological rationale for using antidepressant monotherapies, such as venlafaxine, bupropion, sertraline, fluoxetine, or augmentation of first-line treatment with stimulants or modafinil.