Advances in the mechanistic understanding of atheroma initiation, repair, progression, and rupture have solidified the pivotal role played by the immune system in the pathophysiology of atherosclerotic vascular disease. These mechanistic findings have been extended into humans, with a strong evidence basis for the independent association between elevated blood markers of inflammation and future cardiovascular (CV) events. Investigations with statins as well as more conventional anti-inflammatory medications provide indirect evidence to support the concept that modifying immune responses can improve CV outcomes; however, robust evidence to support the use of anti-inflammatory treatment strategies to manage atherosclerotic vascular disease is still lacking. Such evidence may emerge from a new wave of clinical trials directly exploring the effects of targeted immune modulation on CV risk. These trials will provide key additional insights into atherosclerosis and will help determine the fate of immune modulation as a new treatment strategy in atherosclerotic vascular disease.