Excessive infiltration of immune cells into the kidney is a key feature of acute and chronic kidney diseases. The family of chemokines comprises key drivers of this process. Fractalkine [chemokine (C-X3-C motif) ligand 1 (CX3CL1)] is one of two unique chemokines synthesized as a transmembrane protein that undergoes proteolytic cleavage to generate a soluble species. Through interacting with its cognate receptor, chemokine (C-X3-C motif) receptor 1 (CX3CR1), CX3CL1 was originally shown to act as a conventional chemoattractant in the soluble form and as an adhesion molecule in the transmembrane form. Since then, other functions of CX3CL1 beyond leukocyte recruitment have been described, including cell survival, immunosurveillance, and cell-mediated cytotoxicity. This review summarizes diverse roles of CX3CL1 in kidney disease and potential uses as a therapeutic target and novel biomarker. As the CX3CL1-CX3CR1 axis has been shown to contribute to both detrimental and protective effects in various kidney diseases, a thorough understanding of how the expression and function of CX3CL1 are regulated is needed to unlock its therapeutic potential.