Recent years have seen a tremendous development of our insight into the biology of atherosclerosis and its acute thrombotic manifestations. Inflammation now takes center stage among traditional risk factors as a decisive factor in cardiovascular risk. Consequently, its assessment and modulation have become key to clinical care and fundamental research alike. Plaque macrophages orchestrate many of the inflammatory processes that occur throughout atherogenesis. These cells are characteristically heterogeneous and adopt diverse activation states in response to micro-environmental triggers. In this review, macrophage-mediated inflammation in atherosclerosis sets the scene for a discussion of the gene regulatory mechanisms that facilitate and shape polarized macrophage phenotypes. When applicable, we consider these factors within the context of atherosclerosis and reflect on opportunities for future application.