Fatigue is one of the most common symptoms found in both community and medical care settings. Fatigue may imply a prodromal or residual symptom of major depressive disorder or an adverse reaction to antidepressant treatment. Fatigue may also compromise antidepressant treatment by delaying response to antidepressants. Despite the importance of fatigue as a core depressive symptom, data specific to the effects of fatigue on pharmacological treatment are still lacking. Bupropion is an atypical antidepressant, chemically unrelated to classical agents such as tricyclic antidepressants, selective serotonin reuptake inhibitors and other contemporary antidepressants. With a pharmacological profile that involves neurotransmitter reuptake inhibition, bupropion shares a broad range of biological properties with psychostimulants. The primary action mode of bupropion involves dopaminergic and noradrenergic neurotransmissions rather than serotonergic mechanisms, although its exact pharmacodynamic properties remain uncertain. Hence, it is possible that bupropion may play a role in the treatment of fatigue-related symptoms of major depressive disorder. This paper presents a brief overview of the clinical implications and neurobiology of major depressive disorder-related fatigue, as well as the pharmacological profile of bupropion and currently available clinical data related to its treatment of fatigue-related symptoms of major depressive disorder.