A large body of evidence supports the inflammatory hypothesis of atherosclerosis, and both innate and adaptive immune responses play important roles in all disease stages. Areas covered: Here, we review our understanding of the role of the immune response in atherosclerosis, focusing on the pathways currently amenable to therapeutic modulation. We also discuss the advantages or undesirable effects that may be foreseen from targeting the immune response in patients at high cardiovascular risk, suggesting new avenues for research. Expert commentary: There is an extraordinary opportunity to directly test the inflammatory hypothesis of atherosclerosis in the clinic using currently available therapeutics. However, a more balanced interpretation of the experimental and translational data is needed, which may help address and identify in more detail the appropriate settings where an immune pathway can be targeted with minimal risk.