||DNA double-strand break (DSB) repair gene products play an important role in development and tumor suppression. Mutations in ATM, BRCA1, BRCA2, MRE11, NBN, PALB2, RAD50, RAD51, and XRCC2 result in embryonic lethality or cause pediatric diseases including ataxia-telangiectasia, Fanconi anemia (FA), Nijmegen breakage syndrome (NBS), and other disorders. A DNA DSB can be repaired using two different pathways: nonhomologous end-joining (NHEJ) and homology-directed DSB repair (HDR). Some DSB repair proteins, including ATM, Mre11, RAD50, and Nibrin, function in both pathways. RAD51 and its paralogs only function in HDR. Mre11-Rad50-Nibrin (MRN) complex is a heterohexamer composed of dimers of each protein. The MRN complex is important for early detection of DNA DSBs and activates downstream effectors, most notably the protein kinase ATM. ATM phosphorylates other DNA repair proteins including H2AX. H2AX, phosphorylated histone H2AX, is an important DNA damage signaling factor that helps recruit BRCA1 to damaged DNA. XRCC2 helps promote RAD51 foci through interaction with other RAD51 paralogs RAD51B, RAD51C, and RAD51D to form the BCDX2 complex. FA and NBS-like disorder result from biallelic mutations in XRCC2 and RAD50, respectively. These genetically distinct disorders share many clinical similarities. Bone marrow failure is a key symptom of FA and has been observed in multiple NBS patients. The hematopoietic malignancy acute myeloid leukemia has been observed in patients suffering from FA and NBS. Hormone abnormalities and fertility issues present in both patient populations as do issues with growth and development. Null mutations in RAD50 and XRCC2 are embryonic lethal in humans and mice, so zebrafish was chosen as the model organism to study mutations in each of these genes. Null mutations in related genes (e.g., BRCA2) that result in embryonic lethality in humans and mice are tolerated in zebrafish. Frameshift mutations were generated in rad50 and xrcc2 using transcription activator-like effector nucleases in zebrafish. We recovered the first viable vertebrate model for biallelic null mutations in RAD50 and XRCC2. Study of these mutants might offer unique insights into human disease that have not been possible previously due to a lack of appropriate model systems.