Apolipoprotein (Apo)-based mimetic peptides have been shown to reduce atherosclerosis. Most of the ApoC-II and ApoE mimetics exert anti-atherosclerotic effects by improving lipid profile. ApoC-II mimetics reverse hypertriglyceridemia and ApoE-based peptides such as Ac-hE18A-NH2 reduce cholesterol and triglyceride (TG) levels in humans. Conversely, other classes of ApoE and ApoA-I mimetic peptides and, more recently, ApoJ and LRP1-based peptides, exhibit several anti-atherosclerotic actions in experimental models without influencing lipoprotein profile. These other mimetic peptides display at least one atheroprotective mechanism such as providing LDL stability against mechanical modification or conferring protection against the action of lipolytic enzymes inducing LDL aggregation in the arterial intima. Other anti-atherosclerotic effects exerted by these peptides also include protection against foam cell formation and inflammation, and induction of reverse cholesterol transport. Although the underlying mechanisms of action are still poorly described, the recent findings suggest that these mimetics could confer atheroprotection by favorably influencing lipoprotein function rather than lipoprotein levels. Despite the promising results obtained with peptide mimetics, the assessment of their stability, atheroprotective efficacy and tissue targeted delivery are issues currently under progress.