Although several laboratories have shown that the appearance of naturally occurring suppressor cells in the spleens of neonatal or irradiated mice is temporarily related to the ease of induction of tolerance, the characteristics of these cells and their regulatory functions have been poorly understood until recently. The experimental data reviewed herein suggests that these cells are related to NK cells with regard to surface phenotype but differ with regard to function. The natural suppressor (NS) cells appear only briefly during the early maturation of the lymphoid tissues but can be induced in adults by manipulation of the lymphoid tissues with certain treatment regimens such as total lymphoid irradiation (TLI). In addition, the NS cells can be propagated and cloned in long-term tissue culture, thereby allowing a more detailed investigation of their properties. The cells have the unique feature of inhibiting the antigen-specific cytolytic arm of alloreactive immune responses but leaving intact the antigen-specific suppressive arm. In this way, alloreactions in the regulatory milieu of NS cells generate large numbers of antigen-specific suppressor cells that can maintain tolerance in vivo. Thus the NS cells may play an important role in the development of host-vs-graft and graft-vs-host tolerance in allogeneic bone marrow chimeras during the "window" of tolerance in which neonate and TLI-treated mice accept the infused allogeneic cells.