Neuroendocrine tumors (NETs) are considered an Orphan Disease with a low incidence (<10000/yr) in the United States. Consequently, it has proven very difficult to secure the interest or resources needed to bring newer treatments to the clinical arena for these patients. Although slow to progress in the early stages, once NETs metastasize, the current 5-year survival rate is <30%. Newer, more effective forms of therapy are urgently needed. Targeted radionuclide therapies using single agents such as 131I-metaiodobenzylguanidine (131I MIBG) and 90Y-DOTA-tyr3-Octreotide (90Y-DOTATOC) have shown promise for therapy of small bowel NETs with response rates of 20-40%. Unfortunately, complete responses are notably uncommon, occurring in less than 10% of patients and response duration is often disappointing as well. We propose a Phase I clinical trial combining 90Y-DOTATOC and 131I MIBG that should provide an increase in the radiation dose delivered to tumors without exceeding safe limits for normal kidney and bone marrow. This trial design, based on strong preliminary imaging data and radiation dose modeling, has the potential to provide durable therapeutic benefit for patients with small bowel NETs where other therapeutic strategies fall short. In further basic science studies, we propose an innovative strategy targeting unique G-protein coupled receptor hetero-dimers such as somatostatin receptor/dopamine receptor conjugates that are expressed in NETs. Preliminary data demonstrate that these new targeting agents have high affinity binding to tumor cells; they are predicted to be highly specific for tumor cells as the hetero-dimeric receptors are rarely expressed in normal tissues. Successful development of these unique radionuclide therapies will provide a new paradigm for molecular targeting and image-guided radionuclide therapy that will likely be translated to other malignancies.