This article presents evidence that fibromyalgia patients have alterations in CNS anatomy, physiology, and chemistry that potentially contribute to the symptoms experienced by these patients. There is substantial psychophysical evidence that fibromyalgia patients perceive pain and other noxious stimuli differently than healthy individuals and that normal pain modulatory systems, such as diffuse noxious inhibitory control mechanisms, are compromised in fibromyalgia. Furthermore, functional brain imaging studies revealing enhanced pain-related activations corroborate the patients' reports of increased pain. Neurotransmitter studies show that fibromyalgia patients have abnormalities in dopaminergic, opioidergic, and serotoninergic systems. Finally, studies of brain anatomy show structural differences between the brains of fibromyalgia patients and healthy individuals. The cerebral alterations offer a compelling explanation for the multiple symptoms of fibromyalgia, including widespread pain and affective disturbances. The frequent comorbidity of fibromyalgia with stress-related disorders, such as chronic fatigue, posttraumatic stress disorder, irritable bowel syndrome, and depression, as well as the similarity of many CNS abnormalities, suggests at least a partial common substrate for these disorders. Despite the numerous cerebral alterations, fibromyalgia might not be a primary disorder of the brain but may be a consequence of early life stress or prolonged or severe stress, affecting brain modulatory circuitry of pain and emotions in genetically susceptible individuals.