Although the cause or causes of FM remains to be determined, most researchers believe that the widespread pain, the hallmark symptom of FM, is due to abnormalities in central nervous system function. Moreover, it has been hypothesized that aberrations in the stress response (i.e., corticotrophin-releasing hormone and locus coeruleus-norepinephrine/autonomic nervous systems) may play an important role in symptom expression.

Finally, given the prevalence of emotional/mood disorders in persons with FM, it is also thought that psycho-behavioral factors may contribute to the pathogenesis and/or individual expression of FM. With regard to nervous system function, it is thought that persons with FM experience pain amplification due to abnormal sensory processing in the central nervous system. This is supported by studies showing multiple physiological abnormalities in persons with FM, including: increased levels of substance P in the spinal cord, low levels of blood flow to the thalamus region of the brain, low levels of serotonin and tryptophan and abnormalities in cytokine function.

It has also been suggested that FM may relate to an abnormality in deep sleep. That is, abnormal brain waveforms have been found in deep sleep in many persons with FM. Moreover, tender points can be produced in normal volunteers by depriving them of deep sleep for a few days. By the same token, levels of growth hormone, important in maintaining good muscle and other soft tissue health, and produced almost exclusively during deep sleep, have been found to be low in persons with FM.

Finally, recent studies show that genetic factors may predispose individuals to a genetic susceptibility to FM. For some, the onset of FM is slow; however, in a large percentage of persons the onset is triggered by an illness or injury that causes trauma to the body. These events may elicit an undetected physiological problem already present.