Coronary artery disease arising from atherosclerosis is a leading cause of death and morbidity worldwide. The underlying pathogenesis involves an imbalanced lipid metabolism and a maladaptive immune response entailing a chronic inflammation of the arterial wall. The disturbed equilibrium of lipid accumulation, immune responses and their clearance is shaped by leukocyte trafficking and homeostasis governed by chemokines and their receptors. New pro- and anti-inflammatory pathways linking lipid and inflammation biology have been discovered, and genetic profiling studies have unveiled variations involved in human atherosclerosis. The growing understanding of the inflammatory processes and mediators has uncovered an intriguing diversity of targetable mechanisms that can be exploited to complement lipid-lowering therapies. 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 of ligands and receptors has been explored in search for therapeutic targets to prevent or treat atherosclerosis. Targeting the chemokine system e.g. by disrupting functional heteromer formation or modulating the microRNA-mediated regulation of chemokine expression, offers various entry points for a causative treatment of this widespread and chronic illness. MicroRNAs (miRs) have emerged as key regulators of gene expression typically by repressing the target mRNA, which determines cell fate and function under homeostatic and disease conditions. In particular, the effects of miR-126 and miR-155 in atherosclerosis and chemokine biology will be discussed. Although the approach of directly targeting chemokine receptors has encountered some setbacks, several innovative compounds are currently in an advanced stage of development. Herein, the current standing of this dynamic field is highlighted and the potential advantages and drawbacks of particular strategies are discussed.