The emergence of radioimmunotherapy (RIT) provides a new therapeutic approach in which monoclonal antibodies directed against tumor-specific antigens are used to target therapeutic radioisotopes to sites of disseminated disease. The target cell is eliminated and adjacent tumor cells, to which antibody has not bound, are also killed. To date, 90Y-ibritumomab tiuxetan and 131I-tositumomab are the only FDA-approved, and most extensively studied, radioimmunoconjugates for RIT of non-Hodgkin's lymphoma (NHL). Both 90Y-ibritumomab tiuxetan and 131I-tositumomab utilize an anti-CD20 monoclonal antibody to target radioactivity to malignant B-cells. 90Y-ibritumomab tiuxetan emits pure therapeutic beta radiation, permitting outpatient treatment. The high energy of the beta particles emitted by 90Y (2.3 MeV) achieves a wide-ranging crossfire effect. Approximately 90% of the energy is deposited within 5 mm of the radiation source, which kills not only antibody-bound cells but also neighboring malignant cells within a diameter of up to 12 mm. In addition, the half-life of 90Y matches the in vivo biological half-life of the monoclonal antibody (64 h), with negligible excretion of 90Y in urine. With 90Y-ibritumomab tiuxetan, hematological adverse events correlate with the degree of bone marrow involvement and the bone marrow reserve, rather than with dosimetric parameters, and doses to normal organs and red marrow are well below the accepted limits of 20 Gy to normal organs and 3 Gy to red marrow. A dosing schedule based on patient weight and baseline platelet counts has therefore been developed, and dosimetry is not routinely required. 131I, the isotope used in tositumomab RIT, emits both therapeutic beta radiation and highly penetrating gamma emissions. The lower energy of the beta particles emitted by 131I (0.6 MeV) achieves a crossfire effect of up to 2 mm in diameter, which is used to treat tumors. The gamma radiation emitted by 131I allows both dosimetry and biodistribution studies to be performed; such studies are important because the rate of 131I-tositumomab clearance varies among individuals. Therefore, dosimetry must be performed in each patient before the therapeutic dose of 131I-tositumomab is administered. Similarly, because of this variability in 131I clearance, the dosage of 131I-tositumomab is calculated accordingly for each patient. 131I-tositumomab is a substrate for dehalogenases, which decouple the radioisotope from the antibody moiety, resulting in free, circulating 131I, which can accumulate in the thyroid. Patients who receive 131I-tositumomab therapy are usually hospitalized in radioprotection wards, and are treated by specially trained hospital staff. The administration of RIT requires an integrated team approach, involving nuclear medicine (or, in some countries, radiation oncology), hematology-oncology, nursing, radiopharmacy and radiation safety personnel. Effective collaboration between all members of the RIT team is essential to treatment success, and understanding the properties of these novel agents will facilitate their safe and effective administration.