Zebrafish (Danio rerio) is a bona fide vertebrate model system for understanding human diseases. It allows the transparent visualization of the effects of ionizing radiation and the convenient testing of potential radioprotectors with morpholino-modified oligonucleotides (MO) knockdown. Furthermore, various reverse and forward genetic methods are feasible to decipher novel genetic modifiers of radioprotection. Examined in the review are the radioprotective effects of the proposed radiomodifiers Nanoparticle DF-1 (C-Sixty, Inc., Houston, TX) and Amifostine (WR-2721, Ethyol), the DNA repair proteins Ku80 and ATM, as well as the transplanted hematopoietic stem cells in irradiated zebrafish. The presence of any of these sufficiently rescued the radiation-induced damages in zebrafish, while its absence resulted in mutagenic phenotypes as well as an elevation of time-and dose-dependent radiation-induced apoptosis. Radiosensitizers Flavopiridol and AG1478, both of which block progression into the radioresistant S phase of the cell cycle, have also been examined in zebrafish. Zebrafish has indeed become a favorite model system to test for radiation modifiers that can potentially be used for radiotherapeutic purposes in humans. I. ZEBRAFISH AS AN IDEAL MODEL SYSTEMZebrafish (Danio rerio) has been envisioned as a popular vertebrate model system for studying radioprotection. The extensive forward genetic screens in the 1990s initiated the study of genes affecting zebrafish embryonic development [1,2], and since then a large number of zebrafish mutants exhibiting rare human diseases have been obtained. Recent studies on zebrafish as a model system have provided important insight into various human diseases of oncogenic, neurodegenerative, hematopoietic, and cardiovascular origin [3][4][5][6]. Despite the evolutionary divergence nearly 450 million years ago, the human and zebrafish genome exhibit considerable homology with the conservation of key genes involved in development, signal transduction, cell cycle progression and proliferation, and cell differentiation [7][8][9][10][11]. The effects of ionizing radiation on the two organisms and the extent of phenotypic rescue by radioprotective substances are also similar.Most importantly, zebrafish offers far more practical benefits as a laboratory model system than any other organism. At low cost and with ease of care, large numbers of zebrafish can be maintained in a small space wherein frequent paired matings produce hundreds of embryos at a time. Its optical transparency of embryos allows the visualization of major organ systems during the rapid 3 months of embryonic development. Within 48 hours postfertilization (hpf), major organ systems such as the eyes, brain, heart, liver, muscles, bones, and the GI tract are evident. External embryogenesis also allows experimental manipulations to be conveniently carried out without parental sacrifice. Genetic manipulations *Address correspondence to this author at the Department of Radiation Oncology, Vanderbilt University,...