The roles of chemokine C-X-C motif ligand 12 (CXCL12) and its receptor chemokine C-X-C motif receptor 4 (CXCR4) reveal this chemokine axis as an emerging neuromodulator in the nervous system. In the peripheral and central nervous systems, both CXCL12 and CXCR4 are expressed in various kinds of nociceptive structures, and CXCL12/CXCR4 axis possesses pronociceptive property. Recent studies have demonstrated its critical roles in the development and maintenance of pathological pain, and both neuronal and glial mechanisms are involved in this CXCL12/CXCR4 axis-mediated pain processing. In this review, we summarize the recent development of the roles and mechanisms of CXCL12/CXCR4 axis in the pathogenesis of chronic pain by sciatic nerve injury, human immunodeficiency virus-associated sensory neuropathy, diabetic neuropathy, spinal cord injury, bone cancer, opioid tolerance, or opioid-induced hyperalgesia. The potential targeting of CXCL12/CXCR4 axis as an effective and broad-spectrum pharmacological approach for chronic pain therapy was also discussed.