Fibromyalgia (FM) is a form of nonarticular rheumatism characterized by long-term (> 3 months) and widespread musculoskeletal pain. However, the biophysiology of FM has remained elusive, and the treatment remains mainly empirical. There are numerous hypotheses about the pathophysiology of chronic widespread pain and FM; one includes a possible role of cytokines. Cytokines play a role in diverse clinical processes and phenomena such as fatigue, fever, sleep, pain, stress, and aching. Cytokines related to acute or repetitive tissue injuries may be responsible for long-term activation of spinal cord glia and dorsal horn neurons, thus resulting in central sensitization. Pain, stiffness, and depression in FM could be associated with some signs of inflammatory response system activation. Illumination of the pathophysiologic secrets of FM will result in more effective treatment regimens. We review the role of immune mediators in the pathophysiology of FM.