Cancer-related fatigue (CRF) is a persistent and distressing subjective sense of tiredness or exhaustion related to cancer or cancer treatment that is disproportionate to activity and that interferes with daily functioning. The tiredness can be physical, emotional, or cognitive, and is not relieved by rest. CRF is present during and after cancer treatment and tends to fluctuate over the course of treatment and may persist into the months and years of survivorship after active treatment. CRF is related to sleep disturbance and depression, and this forms a well- established symptom, the fatigue–depression–sleep disturbance symptom cluster. Screening for CRF should be done regularly, starting at diagnosis and continuing through active treatment and survivorship. Cognitive behavioral therapy may be helpful during active treatment, whereas mindfulness-based cognitive therapy can be useful in the posttreatment scenario. This chapter explores the prevalence, contributing factors, assessment, and management of CRF, and also includes a case study and questions about this symptom.