Abstract: Radiopharmaceutical therapy poses a unique set of opportunities and challenges. This is the only form of radiation therapy that can target cancer cells precisely at the cellular level, a key requirement for eliminating circulating tumor cells, disseminated tumor cells, and oligometastases. Yet this distinct advantage over other radiation therapies also poses challenges for harnessing its power and for developing predictive dose response relationships. Each radionuclide (and daughter radionuclide) emits a unique set of radiations with different linear energy transfer and ranges in tissue. These can include Auger electrons, conversion electrons, β particles, x rays, γ rays, and α particles. The relative biological effectiveness (RBE) of these radiations can depend on the subcellular distribution of the radionuclide in the tissue of interest and on radiation dose rate patterns that are dictated principally by radiopharmacokinetics and the range of the emitted radiations. Recent advances have improved our capacity to develop predictive dose response relationships and harness the power of radiopharmaceutical therapy. Among the advancements that will be discussed are the importance of activity distributions, dose rate patterns, and RBE. Recognizing that distribution of the radiopharmaceutical at the cellular level trumps RBE of the radiations emitted, novel approaches to distribute the dose more uniformly over the targeted cell population will also be discussed. Finally, the role of radiation-induced bystander effects in radiopharmaceutical therapy will also be discussed.