Fibromyalgia has a complex etiology, involving the interaction of multiple biological, psychological, and behavioral contributors. Although not completely understood, central augmentation of sensory input, neuroendocrine and neuropeptide abnormalities, family and genetic factors, and psychosocial stressors are thought to play a role. These etiological complexities are reflected in the array of symptom domains, beyond pain, associated with fibromyalgia. Because it is not a discrete disorder, diagnosis relies on assessment of these other symptoms—including sleep disturbance, fatigue, affects on mood, cognitive dysfunction, and chemical sensitivity—and of other common concomitant and overlapping rheumatic and psychiatric disorders, infections, and pain states. Fibromyalgia treatment requires an individualized approach often involving multimodal, multidisciplinary management. Several pharmacotherapies with clinical trial data showing efficacy in treating pain and other symptom domains are available and should be combined with nonpharmacological modalities, including cognitive behavioral therapy and exercise. Although data are limited, combination pharmacotherapy using agents with different mechanisms of action, such as a serotonin/norepinephrine reuptake inhibitor and an alpha-2-delta ligand, may also be a rational approach to address fibromyalgia's multifactoral etiology and symptomatology. Online Access: http://cmeaccess.com/cme/ajm_fibro2_program/index_main.asp?contID=78. This CME Multimedia Activity is also available through the Website of The American Journal of Medicine (www.amjmed.com). Click on the CME Multimedia Activity button in the navigation bar for full access.