Radioimmunotherapy (RIT) is a promising new treatment option for patients with relapsed/refractory non-Hodgkin's lymphoma. Clinical trials have demonstrated that both iodine-131 (131I) and yttrium-90 (90Y) are suitable radionuclides for RIT. Iodine-131 and 90Y differ markedly in their physical properties including half-life, path length, type of energy emissions, intracellular stability, and the organs targeted by the free radionuclide. Both radionuclides can be safely administered in the outpatient setting under current Nuclear Regulatory Commission guidelines. Potential advantages of 131I for RIT include availability, stable chemistry, longer half-life, and an emission spectrum that allows for dosimetric studies and therapy with the same immunoconjugate. By contrast, 90Y has a longer path length and superior intracellular stability compared with 131I. Yttrium-90 may therefore be preferable to 131I for patients with bulky disease, poorly vascularized solid tumors, or when targeting internalized antigens. Although 90Y emits no gamma photon, dosimetry studies for 90Y RIT can be performed using a surrogate radionuclide such as indium-111. Both 131I- and 90Y-labeled anti-CD20 antibodies have demonstrated efficacy in treating relapsed/refractory non-Hodgkin's lymphoma. Further studies are needed, however, to determine if the differences in the pharmacology of 131I and 90Y are clinically relevant.