In their role as small chemotactic cytokines, chemokines are crucial mediators and regulators of leukocyte trafficking during immune surveillance and inflammation. Their involvement in the development and progression of inflammatory diseases has been subject of intense investigation. Concordantly, the chemokine system has been explored in search for therapeutic targets to prevent or treat inflammatory disorders, such as atherosclerosis. Targeting the chemokine system offers various entry points for a causative treatment of this widespread and chronic illness. Although this approach has encountered some setbacks, several innovative compounds are currently in an advanced stage of development. In this review, the current standing of this dynamic field is highlighted and the potential advantages and drawbacks of particular strategies are discussed.