131I-Metaiodobenzylguanidine (MIBG) is a guanethi-dine derivative that is structurally similar to norepi-nephrine, and therefore concentrates in the neurose-cretory granules of catecholamine-secreting cells. Radiolabeled MIBG provides very sensitive and specific visualization of primary and metastatic neuroblastoma by scintigraphy (Shulkin and Shapiro 1998). In an attempt to deliver higher doses of tumor-specific radiotherapy and avoid normal organ toxicity, iodine-131 MIBG therapy has been used in pilot trials since the mid 1980s, with more than 500 children reported in the literature. Initially, it was shown to induce 30-40 % response rate in highly refractory relapsed patients, without significant non-hematologic toxicity (Klingebiel et al. 1991; Matthay et al. 1998; Voute et al. 1991). At low and moderate doses, up to 12 mCi/kg of 131I-MIBG, the main toxicity has been thrombocytopenia, usually self-limited. Phase-I dose escalation studies showed that higher doses, up to 18 mCi/kg, could be administered with bone marrow or peripheral blood stem-cell support to mitigate the neutropenia and thrombocytopenia, but without clinical organ toxicity, excepting a 10-15% incidence of hypothyroidism due to uptake of some free iodide by the thyroid gland (Matthay et al. 1998; Lashford et al. 1992). There are a few reports of patients with secondary leukemia developing after MIBG therapy, but the estimated risk of this problem at 5 years post-therapy is only 4%,lower than with some chemotherapy regimens (Garaventa et al. 2003; Weiss et al. 2003). Despite a number of clinical studies worldwide, dose response to 131I-MIBG has not been firmly established. Recent studies are investigating the use of low dose 131I-MIBG at diagnosis prior to surgical resection (Troncone et al. 1995), or in combination with standard (Mastrangelo et al. 2001)or high-dose myeloablative chemotherapy (Yanik et al. 2002; Klingebiel et al. 1998). New phase-I studies are currently open in the NANT to test the use of double infusion of 131I-MIBG with stem-cell support or further combination with myeloablative chemotherapy and stem cells. Further investigations are required to determine the optimal timing and use of this targeted approach.