Natural antibodies (NAbs), essentially antibodies (Abs) of the IgM isotype present in the circulation of mammalian species, are mainly produced by B-1 lymphocytes independently of external antigenic stimulation. NAbs provide immediate protection against pathogens and play an important role in the host defense mechanism against various stresses. Most of NAbs are poly-reactive (multi-specific or cross-reactive) in nature and recognize specific molecular patterns with no apparent structural similarity. It has been demonstrated that the modified self-proteins, such as oxidized low-density lipoproteins, are important targets of Nabs. In addition, based on the findings that these modified proteins have several properties different from native proteins, including an elevated electronegative potential due to modification of the positively charged amino acid residues, we have proposed that the electronegative potential of antigens might be involved, at least in part, in the recognition by Nabs. In this symposium, I provide a summary of NAbs as a safeguard against covalently modified proteins generated in association with exposome.