Serum bilirubin has been shown to be inversely related to cardiovascular disease (CVD) in both retrospective and prospective studies. Meta-analysis of existing studies has also confirmed that serum bilirubin concentrations are inversely related to CVD. Less information is known about the protective effects of slightly elevated serum bilirubin concentrations. In this review, we will focus primarily on the association of serum bilirubin and CVD and the possible protective roles of bilirubin, heme oxygenase (HO), and bilirubin UDP-glucuronosyltransferase (UGT1A1). HO and biliverdin reductase control the formation of bilirubin, whereas UGT1A1 controls bilirubin conjugation and clearance. Because of the health and therapeutic implications of slightly elevated serum bilirubin concentrations, we will discuss the recent prospective studies on cardiovascular risk in individuals with Gilbert syndrome (GS) as well as those with the UGT1A1*28 allele. Such individuals have decreased hepatic bilirubin UDP-glucuronosyltransferase activity, decreased bilirubin clearance, and increased serum bilirubin concentrations. Lastly, we will discuss some of the therapeutic approaches that could be used to increase serum bilirubin concentrations to prevent CVD and other oxidative and inflammatory diseases.