Atherosclerosis is a chronic inflammatory disease, characterized by the accumulation of oxidized lipoproteins and apoptotic cells, both containing various "oxidation-specific" neoepitopes. Adaptive immune responses to oxidation-specific epitopes have been shown to play an important role in atherogenesis. However, accumulating evidence suggests that these epitopes are also recognized by components of innate immunity, such as scavenger receptors on macrophages, as well as natural antibodies (NAbs). NAbs are mostly of the IgM isotype which are selected by evolution and represent the humoral arc of innate immunity. In my thesis, I provide multiple lines of evidence that oxidation-specific epitopes constitute a dominant, previously unrecognized target of NAbs in both mice and humans. For example, using reconstituted mice expressing solely IgM NAbs, I showed that ∼ 30% of all NAbs bind to model oxidation epitopes, as well as to atherosclerotic lesions and apoptotic cells. Similar observations were made for human natural IgM Abs. Because oxidative processes are ubiquitous, these epitopes might exert selective pressure to expand NAbs, which in turn may play an important role in mediating homeostatic functions consequent to inflammation and cell death. This is demonstrated by the ability of NAbs to facilitate apoptotic cell clearance. These findings provide novel insights into the functions of NAbs in mediating host homeostasis and into their roles in health and diseases, which may lead to novel diagnostic and possibly therapeutic approaches to deal with consequences of oxidative stress such as atherogenesis.