The bystander effect post radionuclide decay describes the biologic response(s) of cells not directly targeted by the radiation insult. Recently, we demonstrated that the specific irradiation of human tumor cells in vivo leads to a bystander effect in subcutaneously growing tumors. These in vivo findings 1) call for the re-evaluation of approaches currently used for estimating the risks to individuals/populations inadvertently exposed internally to radioactivity (e.g., alpha particles) as well as to patients undergoing routine diagnostic nuclear medical procedures, and 2) impact significantly the current dogma for assessing the therapeutic potential of internally administered radionuclides.