Primary immunodeficiency diseases often fully meet the definition of "experiments of nature." Much of the expanding understanding of the lymphoid systems and immunologic functions generated in recent years has been derived from studying patients with primary, generally genetically determined immunodeficiency diseases, as well as other relatively rare secondary immunodeficiency diseases. Increasing knowledge of immunologic defenses, their interacting cellular and molecular components, the evolving details of sequential stages of cellular differentiation, and the nature and control of the cellular and molecular interactions in immunity have now made it possible to define precisely many primary immunodeficiency diseases in full molecular genetic terms. With this wealth of scientific information based on experimental and clinical research, incredible advances have also been made in using bone marrow transplantation (BMT) often as a curative treatment for immunodeficiency, some 60 to 70 other diseases, leukemias, lymphomas, other cancers, and a rapidly expanding constellation of metabolic diseases or enzyme deficiencies. Also, progress in applying allogeneic BMT to prevent, treat, and cure complex autoimmune diseases, primary immunodeficiency diseases and certain forms of cancers, is considered. Further, mixed BMT (syngeneic plus allogeneic) that establishes a form of stable mixed chimerism has also been employed in animal experiments, which revealed that BMT can be used to treat not only immunodeficiency diseases, but also systemic and organ-specific autoimmune diseases, eg, diabetes and erythematous lupus-like diseases. Moreover, performing BMT in conjunction with organ allografts, eg, thymus or pancreatic transplants, has successfully prevented rejection of these allografts, sometimes without recourse to long-term irradiation or toxic chemical immunosuppressive agents. A crucial role for stromal cells in cellular engineering has now also been realized in animal models as a means of preventing graft rejection and promoting full and persistent reconstitution or correction of genetically-based diseases. With all of these achievements, BMT promises continued dramatic and impressive new approaches to clinical and scientific research and reveals an attractive strategy for the treatment and prevention of many currently intractable human diseases. If these achievements can be extended to larger outbred animals and humans, BMT may set the stage for induction of improved immunologic tolerance and for developing treatments for additional intractable human diseases in the 21st century.