Exposure to non-inherited maternal antigens (NIMA) has life-long immunological consequences that may result in tolerance or immunity to these antigens. Gaining understanding of the mechanisms behind these NIMA effects will impact many areas of immunology. This review summarizes new discoveries relevant to autoimmunity and organ transplantation regarding exposure to maternal antigens. In light of these studies, as well as unpublished data from our lab, we conclude that the effect of neonatal exposure to maternal antigens has profound impact on clinical and experimental transplantation and autoimmunity, and important implications for the immune system development.