Atherosclerosis is a chronic inflammatory disease characterized by an imbalance in lipid metabolism and a maladaptive immune response, driven by the accumulation of cholesterol-laden macrophages in the artery wall. The balance of macrophage numbers and their inflammatory phenotype significantly influences plaque fate. This review highlights recent findings on pro- and anti-inflammatory pathways linking lipid and inflammation biology with macrophage retention in plaques, as well as factors promoting their egress from these sites. Key mechanisms include hypercholesterolemia-induced monocytosis, monocyte recruitment to athero-prone arterial sites, foam cell formation, defective cholesterol trafficking, lipid efflux, innate immune activation, macrophage polarization, and macrophage retention and emigration. Understanding these dynamics is crucial for developing therapeutic strategies to modify macrophage behavior towards an atheroprotective state.Atherosclerosis is a chronic inflammatory disease characterized by an imbalance in lipid metabolism and a maladaptive immune response, driven by the accumulation of cholesterol-laden macrophages in the artery wall. The balance of macrophage numbers and their inflammatory phenotype significantly influences plaque fate. This review highlights recent findings on pro- and anti-inflammatory pathways linking lipid and inflammation biology with macrophage retention in plaques, as well as factors promoting their egress from these sites. Key mechanisms include hypercholesterolemia-induced monocytosis, monocyte recruitment to athero-prone arterial sites, foam cell formation, defective cholesterol trafficking, lipid efflux, innate immune activation, macrophage polarization, and macrophage retention and emigration. Understanding these dynamics is crucial for developing therapeutic strategies to modify macrophage behavior towards an atheroprotective state.