Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima, where the balance between pro-inflammatory and inflammation-resolving mechanisms determines clinical outcomes. Infiltration of plasma-derived lipoproteins and their uptake by macrophages lead to foam cell formation, initiating atherosclerotic lesions. Defective efferocytosis of apoptotic and foam cells sustains lesion progression, leading to advanced lesions with necrotic lipid cores. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators (SPMs) derived from omega-3 fatty acids and arachidonic acid, which convert pro-inflammatory macrophages into anti-inflammatory ones. In advanced atherosclerotic lesions, the ratio of SPMs to pro-inflammatory lipids is low, impairing resolution. SPMs, including resolvins, lipoxins, maresins, and protectins, promote efferocytosis, reduce inflammation, and aid tissue repair. Inflammation resolution is also mediated by proteins, gases, and the vagus nerve. Defective resolution leads to chronic inflammation, tissue damage, and plaque vulnerability. Pro-resolving mediators, such as SPMs, can be targeted for therapy to inhibit atherosclerosis. Omega-3 fatty acids, through SPM biosynthesis, may enhance resolution. However, clinical trials have shown limited efficacy of omega-3 supplements in reducing cardiovascular events. The role of macrophages in atherosclerosis is critical, with their life cycle and subsets influencing lesion progression. Macrophages can be pro-inflammatory or anti-inflammatory, depending on their environment and signaling. SPMs and other pro-resolving mediators, such as NO, H2S, and CO, promote resolution by reducing inflammation and enhancing efferocytosis. Understanding these mechanisms is essential for developing therapies to prevent atherosclerosis.Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima, where the balance between pro-inflammatory and inflammation-resolving mechanisms determines clinical outcomes. Infiltration of plasma-derived lipoproteins and their uptake by macrophages lead to foam cell formation, initiating atherosclerotic lesions. Defective efferocytosis of apoptotic and foam cells sustains lesion progression, leading to advanced lesions with necrotic lipid cores. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators (SPMs) derived from omega-3 fatty acids and arachidonic acid, which convert pro-inflammatory macrophages into anti-inflammatory ones. In advanced atherosclerotic lesions, the ratio of SPMs to pro-inflammatory lipids is low, impairing resolution. SPMs, including resolvins, lipoxins, maresins, and protectins, promote efferocytosis, reduce inflammation, and aid tissue repair. Inflammation resolution is also mediated by proteins, gases, and the vagus nerve. Defective resolution leads to chronic inflammation, tissue damage, and plaque vulnerability. Pro-resolving mediators, such as SPMs, can be targeted for therapy to inhibit atherosclerosis. Omega-3 fatty acids, through SPM biosynthesis, may enhance resolution. However, clinical trials have shown limited efficacy of omega-3 supplements in reducing cardiovascular events. The role of macrophages in atherosclerosis is critical, with their life cycle and subsets influencing lesion progression. Macrophages can be pro-inflammatory or anti-inflammatory, depending on their environment and signaling. SPMs and other pro-resolving mediators, such as NO, H2S, and CO, promote resolution by reducing inflammation and enhancing efferocytosis. Understanding these mechanisms is essential for developing therapies to prevent atherosclerosis.