Although systemic radionuclide therapy (SRT) is effective as a palliative therapy in patients with metastatic cancer, there has been limited success in expanding patterns of utilization and in bringing novel systemic radiotherapeutic agents to routine clinical use. Although there are many factors that contribute to this situation, we hypothesize that a better understanding of the radiobiology and mechanism of action of SRT will facilitate the development of future compounds and the future designs of prospective clinical trials. If these trials can be rationalized to the biological basis of the therapy, it is likely that the long-term outcome would be enhanced therapeutic efficacy. In this review, we provide perspectives of the current state of low-dose-rate (LDR) radiation research and offer linkages where appropriate with current clinical knowledge. These include the recently described phenomena of low-dose hyper-radiosensitivity-increased radioresistance (LDH-IRR), adaptive responses, and biological bystander effects. Each of these areas require a major reconsideration of existing models for radiation action and an understanding of how this knowledge will integrate into the evolution of clinical SRT practice. Validation of a role in vivo for both LDH-IRR and biological bystander effects in SRT would greatly impact the way we would assess therapeutic response to SRT, the design of clinical trials of novel SRT radiopharmaceuticals, and risk estimates for both therapeutic and diagnostic radiopharmaceuticals. We believe that the current state of research in LDR effects offers a major opportunity to the nuclear medicine community to address the basic science of clinical SRT practice, to use this new knowledge to expand the use and roles of SRT, and to facilitate the introduction of new therapeutic radiopharmaceuticals.