Cancer-related fatigue (CRF) is the most common and debilitating symptom in patients with cancer. Currently, there are very limited pharmacological interventions to effectively treat CRF. In this article, the authors review various pharmacological interventions for CRF and propose future direction for further research. Methylphenidate is the most studied pharmacological agent for the treatment of CRF. Various pharmacological studies have suggested benefit of corticosteroids, especially in terminally ill patients for a short period. However, recent systematic reviews, meta-analyses, and guidelines recommend caution to using pharmacological agents for CRF as evidence points the use of psychostimulants only in patients with moderate to severe fatigue with advanced cancer or those receiving active cancer therapy, with no evidence in their use in cancer patients who have completed active cancer therapy. Further research is needed.