- This review looks at the emerging field of nontargeted radiation effects and their impact on low-dose radiation risk assessment and radiotherapy. It identifies the major role of experimental hematologists and cytogeneticists in changing the old view of radiation action on living things. It also considers the history of radiobiology, seeking to explain why it is only now that we are considering indirect or nontargeted effects of low doses even though the evidence was there, though buried, in the old literature. Effects receiving major attention worldwide now include genomic instability and bystander effects. The impact of these effects, both on radiotherapy used to treat cancer and on radiation induction of cancer, still need to be clarified. Techniques developed by experimental hematologists are central to these efforts and have been instrumental in causing radiobiologists to consider that a paradigm shift is necessary. Throughout, we make a plea to think "outside the box" since the very construction of a framework necessarily limits our thinking and our experimental design.