A better understanding of the immunological processes governed by cytokines and chemokines has shaped our approach to the design of therapeutics for diseases such as rheumatoid arthritis (RA), atherosclerosis, and other inflammatory disorders. The discovery of chemokines and their receptors as integral components and regulators of inflammation has dramatically contributed to advances in treating these disease states. Among the different classes of chemokines, fractalkine/CX3CL1, with its unique functional and structural characteristics, has been found to participate in inflammation. This viewpoint summarizes the emerging role of fractalkine/CX3CL1 from the historical, functional, and clinical perspective and provides evidence to validate it as a potential therapeutic target in cardiovascular disease, rheumatoid arthritis, as well as other diseases related to vascular inflammation.