The present day use of systemically administered isotopes and conjugated isotopic combinations are reviewed. Administration of 131Iodine in thyroid cancer led to a 97% local control and 50% complete remission of pulmonary metastases. Specificity directed isotopic therapy (metabolic, hormonal, and antibody) is discussed and includes factors such as tumor physiology and isotopic linkage. The clinical results and new knowledge being gained in Hodgkin's disease, non-Hodgkin's, colorectal, hepatoma, intrahepatic biliary and gliomatous cancers are reviewed. The dose response relationship to tumor remission is demonstrated in Hodgkin's treated with 131I antiferritin (40% partial remission) and more recently 90Yttrium antiferritin (50% complete response). Varied routes of administration, the problem of anti-antibody and bone marrow transplantation are discussed. Finally, the challenge to radiobiologists, physicists, chemists, immunologists, nuclear radiologists, and radiation oncologists is emphasized by definition of the new laboratory and clinical approaches being developed in systemic radiation therapy.