Fatigue is a common and highly distressing symptom of cancer associated with reduced quality of life and considerable psychological and functional morbidity. The reported prevalence of cancer-related fatigue ranges from 4% to 91%, depending on the specific cancer population studied and the methods of assessment. Cancer-related fatigue has typically been underreported, underdiagnosed, and undertreated. Fatigue and depression may coexist in cancer patients, and considerable overlap of symptoms occurs. This is partly the reason for the interest in examining the role of psychotropic medications in treating fatigue. Clarifying the relationship between depression and fatigue is necessary to effectively evaluate and treat cancer-related fatigue. Even with International Classification of Diseases criteria, differentiating cancer-related fatigue is difficult. Psychotropic drugs that have been studied for cancer-related fatigue include psychostimulants, wakefulness-promoting agents, and anti-depressants. Methylphenidate has been studied most and seems to be effective and well tolerated despite common side effects. Some preliminary data support using modafinil in cancer-related fatigue with less concern about tolerance or dependence. Antidepressant studies have shown mixed results. Paroxetine seems to show benefit for fatigue primarily when it is a symptom of clinical depression. Bupropion, a norepinephrine/dopamine reuptake inhibitor, may have psychostimulant-like effects, and therefore may be more beneficial for treating fatigue. However, studies are currently limited. Randomized, placebo-controlled trials with specific agents are needed to further assess the efficacy and tolerability of psychotropic medications in the treatment of cancer-related fatigue.