Mutations in the gene encoding the transcription factor Foxp3 lead to fatal autoimmune pathology in mice and humans, which is associated with a deficiency in Foxp3⁺ regulatory T cells (T_reg). It has also been proposed that Foxp3 inactivation in nonhematopoietic tissues, particularly in thymic epithelium, is required for the pathogenesis, because Foxp3 mutant scurfy bone marrow cells fail to transmit the disease to lethally irradiated WT hosts. We demonstrate here that the lack of pathology in these radiation chimeras is due to the presence of radioresistant endogenous Foxp3⁺ T_reg of the host. In addition, chimeras carrying the scurfy mutation only in nonhematopoietic cells exhibit no evidence of autoimmune pathology. Thus, Foxp3 deficiency in nonhematopoietic cells does not contribute to the scurfy disease. Furthermore, our analyses of radiation chimeras revealed that the peripheral T_reg pool is fully and specifically restored and maintained by radioresistant endogenous T_reg or adoptively transferred exogenous T_reg through “homeostatic” proliferation in the absence of T_reg production from scurfy donor bone marrow cells. These results thus provide evidence that the autoimmune pathology in scurfy mice results indeed from a T_reg deficiency and illustrate a robust homeostatic mechanism that strictly controls the size of peripheral T_reg pool by fine-tuning of homeostatic proliferation.