Studies on the immunology of peptidoglycan received impetus from the initial observation that the rabbit Group A-variant streptococcal antisera were a rich source of antibodies to peptidoglycan. Indeed, quantitative precipitin studies revealed concentrations as high as 7-10 mg/ml of antiserum. The amount of antibody after Group A-variant streptococcal immunization is much greater than the amount in the sera following immunization of rabbits with the Group A or C streptococci. Furthermore, earlier studies had shown that the purified peptidoglycan obtained as a residue following extraction of streptococcal cell walls with hot formamide was a poor antigen. Both the hexosamine polymer and the peptide moiety are antigenic. Use of the solid phase synthesized pentapeptide L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala and related similar peptides facilitated the determination of the fine structure of the immunodominant site of pentapeptide. The evidence points to the C-terminal D-Ala-D-Ala as the immunodominant determinant. Because of the similarity of the peptidoglycans of a number of different bacteria, it would be anticipated that they would cross-react immunologically, and this has been shown to be the case. The biological and medical significance of antibodies to peptidoglycan has yet to be determined. Certainly the exposure to this ubiquitous substance which occurs in all the indigenous bacteria of the respiratory and the gastrointestinal tract must mean that from an early age and through advancing years there is a constant stimulation of the immune response to peptidoglycan. Because the immunochemistry of these substances is now firmly established, there is a scientific basis for proceeding with the medical and biological implications of peptidoglycan immunity.