In order for ABO-incompatible organ transplantation to be performed successfully, the antibody response must be targeted. Aggressive strategies are usually required both to remove pre-existing antibodies directed at donor A/B antigens and to suppress further production of antibodies. If this can be accomplished in the short-term, graft accommodation of ABO-incompatible transplants may develop upon eventual re-accumulation of antibodies as the graft acquires resistance to antibody-mediated damage. In contrast to mature individuals, very young infants lack isohemagglutinins due to a natural lag in development of immunity to T cell-independent polysaccharide antigens. This delay in maturation permits a window of safety during which infants can receive ABO-incompatible grafts without the requirement for aggressive immunosuppressive strategies. We have recently demonstrated that ABO-incompatible heart transplantation performed during this stage of immaturity is followed by the spontaneous development of donor-specific B cell tolerance rather than graft accommodation, and that tolerance in this setting occurs by a cellular mechanism of antigen-specific B cell elimination. This finding is strikingly similar to the original descriptions of neonatal T cell tolerance in mice. Our data provide compelling justification that every effort should be made to include juvenile recipients routinely as subjects in tolerance research. Through understanding the mechanisms underlying tolerance in this setting, as with murine models of neonatal tolerance originally described by Medawar and colleagues, it may be possible to expand the potential applications of tolerance strategies to older patient populations.