Atherosclerotic plaque destabilization is a major cause of unstable angina, myocardial infarction, and sudden cardiac death. Macrophages, which are an essential component of unstable plaques, play a pivotal role in the destabilization process, whereas smooth muscle cells contribute to plaque stability. Selective removal of macrophages is therefore an interesting pharmacological objective to stabilize vulnerable, rupture-prone lesions. Pharmacological agents such as clodronate, nitric oxide donors, mammalian target of rapamycin (mTOR) inhibitors, protein synthesis inhibitors, and statins, that are capable of selectively depleting macrophages in atherosclerotic plaques without affecting smooth muscle or endothelial cells, have recently been identified. This review focuses on the mechanism of action of these drugs as well as on the potential pitfalls of drug-induced macrophage depletion.