Up to 50% of Americans will develop cancer, and >90% of patients will experience cancer-related fatigue (CRF) at some point in their disease course. Patients describe CRF as devastating to many life domains, degrading their vocational, familial, and societal roles. This article describes current best efforts to define CRF and to characterize its epidemiology using these definitions. In addition, the article will outlines assessment tools, proposed mechanisms, associated symptoms, and treatment strategies. Readers are offered highly more comprehensive references relating to specific aspects of CRF throughout.