Cancer-related fatigue (CRF) is commonly reported by patients with cancer before, during, and after treatment. It is a persistent sense of tiredness that interferes with function, is distressing, and requires monitoring and, possibly, treatment. Fatigue assessment requires objective measures and self-reports, such as Functional Assessment of Cancer Therapy–Fatigue. Significant contributors to CRF include anemia, pain, insomnia, depressive symptoms, and elevated BMI. Elevated inflammatory cytokines, diabetes mellitus, cortisol, and cellular dysregulation have been associated with CRF. None is causal. Effective treatments include correction of other medical problems, especially anemia, cognitive behavioral therapy, exercise, modafinil, and corticosteroids for short-term use.