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Pain is associated with myriad medical conditions and affects millions of Americans. Chronic pain is one of the most common reasons prompting visits to healthcare providers; collectively, it possibly disables more people annually than heart disease and cancer combined. Primary goals of treating patients with chronic pain are to reduce pain as much as possible and facilitate functional restoration. When chronic pain becomes a disease state, it can be controlled, but, at present, it cannot be cured. Better understanding of the pathophysiology of acute and chronic pain has led to numerous advances in pharmacologic management of painful disorders, including low back pain, migraine headache, fibromyalgia, postherpetic neuralgia, osteoarthritis, rheumatoid arthritis, and cancer-related neuropathic pain. This presentation reviews the available agents and how to use them rationally, either singly or in combination, so practitioners can treat patients with chronic pain as effectively as possible.