During inflammation, chemokines play a central role by mediating the activation of inflammatory cascade responses in tissue injury. Among more than 200 chemokines, CX3CL1 is a special chemotactic factor existing in both membrane-bound and soluble forms. Its only receptor, CX3CR1, is a member of the G protein-coupled receptor superfamily. The CX3CL1/CX3CR1 axis can affect many inflammatory processes by communicating with different inflammatory signaling pathways, such as JAK-STAT, Toll-like receptor, MAPK, AKT, NF-κB, Wnt/β-catenin, as well as others. These inflammatory networks are involved in much pathology. Determining the crosstalk between the CX3CL1/CX3CR1 axis and these inflammatory signaling pathways could contribute to solving problems in tissue injury, and the CX3CL1/CX3CR1 axis may be a better therapeutic target than inflammatory signaling pathways for preventing tissue injury due to the complexity of inflammatory signaling networks.