In this systematic review, we present a comprehensive and up-to-date systematic review of the literature as it relates to the efficacy and effectiveness of spinal manipulation or mobilization in the management of cervical, thoracic, and lumbar-related extremity pain. There is moderate quality evidence that spinal manipulation is effective for the treatment of acute lumbar radiculopathy. The quality of evidence for chronic lumbar spine–related extremity symptoms and cervical spine–related extremity symptoms of any duration is low or very low. At present, no evidence exists for the treatment of thoracic radiculopathy. Future high-quality studies should address these conditions.