This chapter describes what is currently known about cancer-related fatigue (CRF) in cancer survivors. Significance and prevalence rates are reviewed and definitions are discussed within the context of the need to develop case definitions and phenotypes to advance the science and practice of CRF. Two conceptual frameworks/models for CRF are identified based on emerging evidence that unify the seemingly disparate underlying mechanisms proposed in the literature. While further testing of these models and their propositions are needed, these models can be used to guide future studies investigating CRF and its underlying relationships with other symptoms such as pain, depression, and insomnia. The National Comprehensive Cancer Network (NCCN) guidelines for the assessment and management of CRF are reviewed. Particular emphasis is given to the assessment and management of the common contributing and treatable factors associated with CRF (i.e., anemia, comorbidities, deconditioning, emotional distress, nutrition, pain, sleep disturbance/insomnia, symptom clusters, and cognitive impairment). Barriers to guideline adherence and exercise prescription are discussed, and patient and provider education is emphasized.