Abstract: The knockout of the chemokine C-X-C motif chemokine receptor 4 (CXCR4) in growth-stimulated retinal ganglion cells (RGCs) has a multiplicative effect on optic nerve regeneration. C-X-C motif chemokine ligand 12 (CXCL12), the exclusive ligand of CXCR4, is expressed and axonally transported by an RGC subpopulation, releasing the chemokine at the lesion site. CXCL12 attracts injured axons of a CXCR4-positive RGC subpopulation, mostly αRGC, thereby preventing extension into the distal nerve. Knockout of either CXCR4 or CXCL12 in RGCs overcomes the axonal entrapment at the lesion site and enables long-distance regeneration. Thus, CXCL12/CXCR4-dependent attraction of axons contributes to the failure of optic nerve regeneration. Here we briefly cover CXCR4-based neural motility, current mechanistic background, and future perspectives in central nervous system (CNS) regeneration.