This article reviews current findings regarding the pathophysiologic abnormalities that contribute to the enhanced pain responses of individuals with fibromyalgia as well as the relationships between fibromyalgia and commonly co-occurring disorders. Risk factors for fibromyalgia or enhanced pain responses include genetic and family influences, environmental triggers, and abnormal neuroendocrine and autonomic nervous system function. These risk factors also are associated with several disorders that frequently co-occur with fibromyalgia, such as major depressive disorder, migraine, and irritable bowel syndrome. Indeed, fibromyalgia and these co-occurring conditions may be part of a group of affective spectrum disorders that share important common, and perhaps heritable, causal factors. Recent research strongly suggests that alterations in central processing of sensory input also contribute to the cardinal symptoms of fibromyalgia, persistent widespread pain and enhanced pain sensitivity. Exposure to psychosocial and environmental stressors, as well as altered autonomic nervous system and neuroendocrine responses, also may contribute to alterations in pain perception or pain inhibition. Understanding the pathophysiology of fibromyalgia and co-occurring disorders may help clinicians provide the most appropriate treatment to their patients.