The basic biological principle for 131I treatment of patients with thyroid cancer is the ability of well-differentiated tumor cells to uptake iodine. The absorption of adequate activities of radioiodine may sterilize primary tumor cells and the metastatic deposits. The basic factors which determine the effectiveness of radioiodine treatment include the effective half-life of 131I, the discrete energy of its beta decay, the effective range of emitted beta-rays, the activity of individual therapeutic doses, the intrinsic ability of tumor to uptake radioiodine, and the absorbed total radiation dose. The biological factors, which contribute to the effectiveness of radioiodine treatment, can be referred to "five Rs" of radiobiology: radiosensitivity, repair, redistribution, reoxygenation, and repopulation. The theoretical radiobiological considerations suggest that improvements in therapeutic indexes of radioiodine treatment are possible, e.g. by unconventional fractionation of 131I, or by combining the radionuclide therapy with external-beam irradiation. The net effect of such strategies in the clinic is, however, often unpredictable, and remains investigational and controversial. This illustrates the need for improved design of new research in clinical and experimental radiobiology of radioiodine treatment.