Fatigue and sleepiness (hypersomnia) are symptoms that are highly prevalent in patients with major depressive disorder (MDD). Individuals who complain of fatigue but do not have diagnosable depression are at a higher risk for developing MDD later in life than individuals who do not complain of fatigue. Fatigue and sleepiness also appear to be particularly difficult to treat, as they are often encountered as residual symptoms among MDD patients who have remitted following treatment with standard antidepressants. There are 3 main approaches for addressing fatigue and sleepiness in depression: first, prescribing antidepressant medications that are less likely to exacerbate these particular symptoms; second, prescribing antidepressant medications that are more likely to resolve these symptoms; third, the use of adjunctive treatments to specifically target residual fatigue and sleepiness in depression.