Atherosclerosis is now widely recognized as a chronic inflammatory disease that involves innate and adaptive immune responses. Both cellular and humoral components of the immune system have been implicated in atherogenesis. Natural antibodies can be considered humoral factors of innate immunity, and their functional role in health and disease has been reexamined in recent years. Natural antibodies exhibit a remarkably conserved repertoire that includes a broad specificity for self-antigens. For this reason, they are believed to be a product of natural selection and have been suggested to play an important role in "housekeeping" functions. Recent evidence has revealed that oxidation-specific epitopes are important and maybe immunodominant targets of natural antibodies, suggesting an important function for these antibodies in the host response to consequences of oxidative stress, for example, to the oxidative events that occur when cells undergo apoptosis. This review will focus on these recent findings and discuss the emerging evidence for an important role of natural antibodies in atherogenesis.