Here we present a unique insight into the mechanisms and physiological relevance of macrophage polarization in atherosclerosis: Akt1 and Akt2 isoforms are highly homologous and functionally redundant in Akt signaling, but genetic deletion of these isoforms in macrophages results in the development of isoform-specific opposing phenotypes with differential effects in both early and advanced atherosclerosis. Here, AKT2 is linked to atherosclerosis.