Plasma HDL levels have an inverse relationship to coronary artery disease (CAD) risk, which led to the idea that increasing HDL levels therapeutically would ameliorate atherosclerosis. Human genetic deficiency of CETP caused markedly elevated HDL and moderately reduced non-HDL cholesterol levels, suggesting that CETP inhibitors might produce cardiovascular benefit. The CETP inhibitor anacetrapib reproduced the phenotype of homozygous CETP deficiency and showed a highly significant benefit for CAD in the REVEAL trial. However, the magnitude of this effect was moderate, and the mechanism of benefit remains unclear. Insights into the mechanisms underlying macrophage cholesterol efflux and reverse cholesterol transport have come from monogenic human disorders and transgenic mouse studies. In particular, the importance of the ATP binding cassette transporters ABCA1 and ABCG1 in promoting cholesterol efflux from myeloid and other hematopoietic cells has been shown and linked to aberrant myelopoiesis and macrophage inflammation. Recent studies have shown that myeloid deficiency of ABCA1 and ABCG1 leads to macrophage and neutrophil inflammasome activation, which in turn promotes atherosclerotic plaque development and notably the formation of neutrophil extracellular traps (NETs) in plaques. In addition, clonal hematopoiesis has emerged as an important CAD risk factor, likely involving macrophage inflammation and inflammasome activation. Further elucidation of the mechanisms linking plaque accumulation of cholesterol and oxidized lipids to myeloid cell inflammation may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for CAD. •Plasma HDL has athero-protective functions, related to its ability to promote efflux of cholesterol from macrophage foam cells.•Cholesterol efflux pathways suppress excessive myelopoiesis, macrophage inflammation, inflammasome activation and NETosis.•Therapeutic targeting of beneficial HDL functions that increase cholesterol efflux has strong potential to reduce CHD.