Recent publications reveal the mechanism of action of apolipoprotein A-I (apoA-I) mimetic peptides to be the remarkable binding affinity that oxidized lipids have for these peptides compared with apoA-I. There was no difference in the binding affinity of oxidized lipids or in peptide efficacy in reducing inflammation and atherosclerosis in rabbits injected with peptides synthesized from all D- or all L-amino acids. The apoA-I mimetic peptide 4F increased the formation of pre-beta high-density lipoprotein, increased cholesterol efflux, and reduced lipoprotein oxidation in vitro; it increased antioxidants and vascular repair in type 1 diabetic rats; it improved vasodilation, oxidative stress, myocardial inflammation, and angiogenic potential in a mouse model of scleroderma; it reduced renal inflammation in low-density lipoprotein receptor-null mice fed a Western diet; it reduced arthritis in a rat model; it reduced adiposity, increased adiponectin levels, and improved insulin sensitivity in obese mice; and it improved high-density lipoprotein inflammatory properties in humans with coronary heart disease.