Cancer-related fatigue (CRF) is the most commonly reported symptom in patients with cancer with a prevalence up to 100%. It has a significant negative impact on quality of life. An effective management of CRF could significantly reduce the disease burden associated with cancer and its treatment. Unfortunately, the underlying pathophysiology is very complex and not uniform. This article reviews the possible therapy of contributing factors, nonpharmacological treatment, such as exercise and psychosocial interventions, and pharmacologic approaches in managing CRF. Numerous drugs, such as psychostimulants (methylphenidate, dexamphetamines, modafinil and pemoline), antidepressants, corticosteroids, L-carnitine, donepezil and guarana have been studied. Methylphenidate, modafinil and guarana show the most promising results so far. However, additional randomized, placebo-controlled trials are needed to determine the benefit of these and other drugs in the treatment of CRF.