Purpose of Review <p>This review examines the impact of genetic variation in chemokines and their receptors on the risk of atherosclerosis and adverse cardiovascular outcomes.</p> Recent Findings <p>Human genetic studies have identified associations between variants in multiple chemokines and chemokine receptor loci and atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease and myocardial infarction, carotid atherosclerosis and large-artery atherosclerotic stroke, as well as peripheral artery disease. Among chemokine pathways, the most consistent evidence implicates the CCL2-CCR2, CXCL12-CXCR4, and CXCL10-CXCR3 axes. Triangulation with experimental, epidemiological, and human tissue data supports the potential of targeting these pathways to reduce vascular inflammation, promote plaque stabilization, and lower ASCVD risk.</p> Summary <p>Recent proof-of-concept trials have demonstrated the efficacy of anti-inflammatory therapeutics in atherosclerosis. As the field moves towards a newer generation of atherosclerosis-specific anti-inflammatory agents, human genetic evidence supports targeting chemokine pathways, particularly those governing immune cell trafficking, as a promising therapeutic strategy. These findings provide a strong background for clinical trials assessing anti-chemokine drugs for the prevention of cardiovascular events.</p> Graphical Abstract <p>Graphical overview of the role of genetic variation in the chemokine network in prioritization of drug targets for atherosclerotic cardiovascular disease. GWAS – Genome-wide association studies, LoF – Loss of function, ASCVD – atherosclerotic cardiovascular disease. Created in <a href="https://BioRender.com">https://BioRender.com</a>.</p> <p></p>