Abstract: The chemokine CXCL12/stromal cell-derived factor 1 (SDF-1) is one of the chemokines that have been described in immune system. Its main functions include chemotaxis for lymphocytes and macrophages, migration of hematopoietic cells from fetal liver to bone marrow and the formation of large blood vessels. Accumulating evidences indicate that disease associated or injury-induced functional expression of CXCL12/CXCR4 signaling in both neural and non-neural elements of peripheral nervous system play important roles in the pathophysiology of chronic pain. Under normal conditions, CXCL12 can also act in central nerve system (CNS) as a classical neuromediator and can modulate the activity of several neuroendocrine networks. However, during pathological state (altered immune response or inflammation), due to its local production by glial and/or endothelial cells and/or its diffusion and transportation through the vascular circulation, enhanced concentrations of CXCL12 and/or its presence at unusual sites can affect neuronal and neuroendocrine activities and modify the functioning of the brain, leading to pathological behaviors and/or neurotoxicity. In conclusion, CXCL12/CXCR4 signaling is a potential target for the development of novel therapeutics.