Combined chemical and autoradiographic studies in rats injected with tritiated thymidine indicate that acute red cell sequestration stimulates reticuloendothelial (RE) proliferation. In the spleen DNA synthesis is most markedly stimulated in the marginal zone which is also the initial site of red cell sequestration. This proliferative response involves several division steps and eventuates in a colonization of the red pulp with increased numbers of all cell lines native to the spleen. In both spleen and liver there occurs also a generalized stimulation of division in the macrophages and littoral cells which involves only 1 or 2 division steps. Chronic compensated hemolytic anemia achieved in rats by injections of phenylhydrazine caused functional overactivity of the RE system, including increased sequestering function and hypergammaglobulinemia. This splenic hyperplasia did not entirely regress after cessation of the injections. In man the splenomegaly of a chronic non-immunological hemolytic anemia, hereditary spherocytosis, was found to involve a marked (average: 8-fold) hyperplasia of all spleen cellular elements. Neither the acute nor chronic proliferative reaction appears to arise from immunological or "toxic" stimuli and the findings support the view that the size of the RE system is a function of its particulate "work load." It is suggested that the cytoproliferative aspects of immune responses may depend upon non-specific, usually particulate stimulation. After prolonged stimulation, hyperplasia of the RES may become partly irreversible.