Although the general radiobiologic principles underlying external beam therapy and radionuclide therapy are the same, there are significant differences in the biophysical and radiobiologic effects between the 2 types of radiation. In addition to the emission of particulate radiation, targeted radionuclide therapy is characterized by (1) extended exposures and, usually, declining dose rates; (2) nonuniformities in the distribution of radioactivity and, thus, absorbed dose; and (3) particles of varying ionization density and, hence, quality. This review explores the special features that distinguish the biologic effects consequent to the traversal of charged particles through mammalian cells. It also highlights what has been learned when these radionuclides and radiotargeting pharmaceuticals are used to treat cancers.