This review highlights the protective roles of bilirubin against the atherosclerotic process. Bilirubin belongs to the superfamily of tetrapyrrolic compounds formed during heme catabolism. Although for decades bilirubin was considered to be a harmful waste product, recent epidemiologic studies have shown that serum bilirubin levels have consistently been inversely associated with cardiovascular disease (CVD), as well as cardiovascular risk factors such as metabolic syndrome and diabetes. These clinical studies are supported by in vitro and in vivo experimental data and have demonstrated that bilirubin not only has an ability to scavenge overproduced reactive oxygen species and inhibit vascular smooth muscle cell proliferation but, additionally, has anti-inflammatory effects. In this review, we will discuss the inverse association of serum bilirubin and CVD and cardiovascular risk factors established in various clinical studies. We also review detailed experimental studies about the effect of bilirubin on atherosclerotic processes. In vitro, animal and human studies have proved that bilirubin inhibits oxidation of cholesterol which is an important step of atherosclerosis. Bilirubin attenuates chemotactic activity of monocytes and strongly inhibits adhesion of leukocytes to venule and production of pro-inflammatory cytokines. Bilirubin has inhibited serum-driven smooth muscle cell cycle progression at the G1 phase. Lastly, we will discuss briefly the influence of bilirubin on lipoprotein composition and endothelial dysfunction.