Shamini Jain,1 Courtney Boyd,2 Lavinia Fiorentino,1 Raheleh Khorsan,3 Cindy Crawford2 1Department of Psychiatry, University of California San Diego, San Diego, CA, USA; 2Samueli Institute, Alexandria, VA, USA; 3Samueli Institute, Corona Del Mar, CA, USA Purpose: While fatigue, sleep disturbance, and depression often co-occur in breast cancer patients, treatment efficacy for this symptom cluster is unknown. A systematic review was conducted to determine whether there are specific interventions (ie, medical, pharmacological, behavioral, psychological, and complementary medicine approaches) that are effective in mitigating the fatigue–sleep disturbance–depression symptom cluster in breast cancer patients, using the Rapid Evidence Assessment of the Literature (REAL©) process. Methods: Peer-reviewed literature was searched across multiple databases; from database inception – October 2011, using keywords pre-identified to capture randomized controlled trials (RCT) relevant to the research question. Methodological bias was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) 50 checklist. Confidence in the estimate of effect and assessment of safety were also evaluated across the categories of included interventions via the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology. Results: The initial search yielded 531 citations, of which 41 met the inclusion criteria. Of these, twelve RCTs reported on all three symptoms, and eight of these were able to be included in the GRADE analysis. The remaining 29 RCTs reported on two symptoms. Studies were of mixed quality and many were underpowered. Overall, results suggest that there is: 1) promising evidence for the effectiveness of various treatment types in mitigating sleep disturbance in breast cancer patients; 2) mixed evidence for fatigue; 3) little evidence for treating depression; and 4) no clear evidence that treatment of one symptom results in effective treatment for other symptoms. Conclusion: More high-quality studies are needed to determine the impact of varied treatments in mitigating the fatigue–sleep disturbance–depression symptom cluster in breast cancer patients. Furthermore, we encourage future studies to examine the psychometric and clinical validity of the hypothesized relationship between the symptoms in the fatigue–sleep disturbance–depression symptom cluster. Keywords: fatigue, sleep disturbance, depression, symptom cluster, breast cancer, Rapid Evidence Assessment of the Literature