Cardiovascular diseases represent 1 of the main causes of death worldwide, and atherosclerosis is 1 of the major contributors leading to ischemic heart disease. Macrophages actively participate in all stages of atherosclerosis development, from plaque initiation to the transition to vulnerable plaques. Macrophage apoptosis, in particular, has been recognized as a critical step in the formation of the necrotic core, a key characteristic of unstable lesions. In this review, we discuss the role of macrophage apoptosis and clearance of apoptotic cells by efferocytosis in the development of atherosclerosis, with particular emphasis on their contribution to the development of the necrotic core and the clinical implications of this process for plaque stabilization. We consider the molecular triggers of macrophage apoptosis during atherogenesis, the role of endoplasmic reticulum (ER) stress, the roles of key cellular mediators of apoptosis and efferocytosis, and mechanisms of defective efferocytosis in the progression of atherosclerotic plaques. Finally, we discuss the important clinical implications of rapidly evolving macrophage science, such as novel approaches to imaging vulnerable atherosclerotic plaques with macrophage-sensitive positron emission tomography and magnetic resonance imaging, the role of macrophages in mediating beneficial pleiotropic actions of lipid-lowering therapies, and novel therapeutic modalities targeting ER stress, autophagy, and deficient efferocytosis. Advances in understanding the critical role of macrophages in the progression and destabilization of atherosclerosis have the potential to greatly improve the prevention and management of atherosclerotic diseases over the next decade.