Targeted systemic radiotherapy constitutes the systemic administration of a radioactive agent that targets a molecule expressed preferentially on cancer cells. The archetypal such therapy is 131-iodine ( 131I) therapy for differentiated thyroid cancers. Radiotherapy typically delivers a calculated radiation-absorbed dose to tumor that takes into account (contiguous) normal tissue. Systemic radiotherapy development currently uses schema more analogous to chemotherapy—a radioactivity estimate that does not cause any irreversible toxicity. Historically, arbitrary amounts of radioactivity shown to be effective, on the basis of retrospective review, were used for thyroid cancer therapy with 131I as well as for neuroendocrine tumor therapy with 131I-labeled meta-iodo-benzylguanidine (MIBG). Their established safety record has led to adaptations that include repeat therapies with nontoxic amounts of radioactivity. There remains, however, a lack of clear understanding of the safety limits of systemic targeted radiotherapy. This is probably most true in systemic therapy with MIBG in adult neuroendocrine tumors. Bone marrow is the primary critical organ for most targeted systemic radiotherapy; second organ involvement may be renal, as with MIBG and targeted radiopeptide therapy, or pulmonary, as with radioimmunotherapy. Most therapies have tended toward multiple administrations of subtoxic amounts of radioactivity. Therapy with MIBG in pheochromococytoma as well as targeted radiopeptide therapy in medullary thyroid cancer has followed this model. Radioimmunotherapy appears very promising; a definitive Phase 2 study needs completion. All therapy has shown promise in extending disease survival (as compared with historical controls), with few major structural (or biochemical) responses. This review will attempt to compliment the excellent existing literature by providing an overall systemic therapeutic approach to this promising endeavor.