Cancer-related fatigue (CRF) is a significant clinical problem for more than 10 million adults diagnosed with cancer each year worldwide. No "gold standard" treatment presently exists for CRF. To provide a guide for future research to improve the treatment of CRF, the authors conducted the most comprehensive combined systematic and meta-analytic review of the literature to date on non-pharmacological (psychosocial and exercise) interventions to ameliorate CRF and associated symptoms (vigor/vitality) in adults with cancer, based on 119 randomized controlled trials (RCTs) and non-RCT studies. Meta-analyses conducted on 57 RCTs indicated that exercise and psychological interventions provided reductions in CRF, with no significant differences between these 2 major types of interventions considered as a whole. Specifically, multimodal exercise and walking programs, restorative approaches, supportive-expressive, and cognitive-behavioral psychosocial interventions show promising potential for ameliorating CRF. The results also suggest that vigor and vitality are distinct phenomena from CRF with regard to responsiveness to intervention. With improved methodological approaches, further research in this area may soon provide clinicians with effective strategies for reducing CRF and enhancing the lives of millions of cancer patients and survivors.