Despite extensive research, the pathogenesis of pain in fibromyalgia syndrome is incompletely understood. Fibromyalgia pain is consistently felt in deep tissues including ligaments, joints and muscles. Increasing evidence points towards these tissues as relevant contributors of nociceptive input that might either initiate or maintain central sensitization, or both. Persistent or intense nociception can lead to transcriptional and translational changes in the spinal cord and brain resulting in central sensitization and pain. This mechanism represents a hallmark of fibromyalgia and many other chronic pain syndromes, including irritable bowel syndrome, temporomandibular disorder, migraine, and low back pain. Importantly, after central sensitization has been established, only minimal nociceptive input is required for the maintenance of the chronic pain state. Other factors, including pain-related negative affect, have been shown to significantly contribute to clinical fibromyalgia pain. An improved understanding of the mechanisms that characterize central sensitization and clinical pain will provide new approaches for the prevention and treatment of fibromyalgia and other chronic pain syndromes.