Cancer-related fatigue is reported by patients to be the most distressing and persistent symptom experienced during and after treatment. Unrelieved fatigue often accompanies other symptoms and leads to decreased physical functioning and lower health-related quality of life. Various factors, including daytime sleepiness and sleep disturbances, have been reported to influence perceptions of fatigue. This article shares current knowledge about the relationships among cancer-related fatigue, sleep disturbances, and daytime sleepiness, and makes recommendations for routine screening, assessment, and interventions to modify fatigue through optimizing sleep quality in adult cancer patients. Evidence is reviewed for nonpharmacologic and pharmacologic interventions for optimizing sleep quality in patients with acute or chronic insomnia secondary to medical illnesses, including cancer. A summary of interventions is presented that focuses on optimizing sleep quality in attempt to lower fatigue. These interventions may be helpful for adult cancer patients experiencing insomnia but will require further testing to establish their efficacy in this population. Recommendations for research are provided, including the need to increase knowledge on the relationships among fatigue, sleep disturbances, daytime sleepiness, and other symptoms in various disease sites, stages, and treatments of cancer and the need for further testing of the measurements used for the evaluation of sleep quality in clinical practice and research.