Chronic fatigue syndrome and/or fibromyalgia (CFS/FM) consists of highly overlapping, medically unexplained symptoms, including long-lasting fatigue, effort intolerance, cognitive dysfunction, and widespread pain and tenderness. CFS/FM often seems to be triggered by infections and physical trauma, but depression, sleep disturbances, and personality may also be involved. Moreover, dysregulation of the stress system, the immune system, and central pain mechanisms may determine the pathophysiology of the illness, leading to a loss of capacity to adapt to all kind of stressors. CFS/FM patients can be best helped by a pragmatic and individualized approach aimed at adjusting lifestyle and optimizing self-care, which in the long run may contribute to a restoration of physical and mental adaptability. Future psychiatric research into CFS/FM should focus on the complex interrelationships among pain/fatigue, stress/depression, and personality, as well as on processes of therapeutic change and the advantages of customized treatment.