Targeted radiotherapy of neural crest-derived tumors such as pheochromocytoma (PC), neuroblastoma (NB) and thyroid medullary carcinoma (TMC) exploits the pharmacological properties of an isotope-labelled “molecular bullet” showing a high metabolic affinity and selectivity for sympathetic neurons and chromaffin cells. The key event for this selective uptake is the expression of specific transporter molecules at the plasma membrane. ¹³¹lodine- labelled metaiodobenzylguanidine (MIBG) is thus far the most extensively used radiopharmaceutical, its uptake being mediated mainly by the noradrenaline transporter. A large series of in vitro experiments shows that the ability of neuroectodermal cells to functionally express this transporter parallels their degree of maturity. Hence, the induction of differentiation of these tumor cells in vitro strongly increases their MIBG uptake and intracellular half-life, thus allowing for a more effective radiotherapeutic effect. Contrary to PC cells, which store MIBG into secretory granules and vesicles, NB cells acquire or enhance only their ability to transport MIBG from the extracellular medium upon differentiation-promoting stimuli, whereas an increased storage has not yet been achieved in vitro. The synergistic combination of differentiative treatment and targeted radiotherapy could represent a novel therapeutic strategy against tumors.