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Science has tremendously advanced our understanding of the pathophysiology of chronic pain. Breakthrough findings include functional and structural brain changes, neuro-inflammation, sensory changes, immune alterations, psychological problems, neurocognitive disorders, stress intolerance, sleep impairments, and (epi)genetic changes found in patients with chronic pain. This Journal of Clinical Medicine Boutique Special Issue focuses on the broad field of the biology of chronic pain in humans. It includes invited state-of-the-art papers addressing key biological processes in patients with chronic pain and original research reports. The state-of-the-art papers were written by leading experts and key opinion leaders in the field. This Special Issue contributes to an exciting area of tremendous advancements and breakthrough research.