There is an interdependent relationship between insomnia and fatigue in the medical literature, but both remain distinct entities. Insomnia entails problematic sleep initiation, maintenance, or restoration with an accompanying decrease in perceived daytime function. Lethargy is a symptom that has a wide differential diagnosis that heavily overlaps with cancer-related fatigue; however, insomnia may contribute to worsened fatigue and lethargy in cancer patients. Insomnia is a major risk factor for mood disturbances such as depression, which may also contribute to lethargy in this at-risk population. The pathophysiology of fatigue and insomnia is discussed in this review, including their differential diagnoses as well as the emerging understanding of the roles of neurotransmitters, branched-chain amino acids, and inflammatory cytokines. Treatment approaches for insomnia and fatigue are also discussed and reviewed, including the role of hypnotics, psychotropics, hormonal agents, and alternative therapies.