Inherited defects in components of the nonhomologous end-joining DNA repair mechanism produce a T–B–NK+ severe combined immunodeficiency disease (SCID) characterized by heightened sensitivity to ionizing radiation. Patients with the radiosensitive form of SCID may also have increased short- and long-term sensitivity to the alkylator-based chemotherapy regimens that are traditionally used for conditioning before allogeneic hematopoietic cell transplantation (HCT). Known causes of radiosensitive SCID include deficiencies of Artemis, DNA ligase IV, DNA-dependent protein kinase catalytic subunit, and Cernunnos-XLF, all of which have been treated with HCT. Because of these patients’ sensitivity to certain forms of chemotherapy, the approach to donor selection and the type of conditioning regimen used for a patient with radiosensitive SCID requires careful consideration. Significantly more research needs to be done to determine the long-term outcomes of patients with radiosensitive SCID after HCT and to discover novel nontoxic approaches to HCT that might benefit those patients with intrinsic radiosensitivity and chemosensitivity as well as potentially all patients undergoing an HCT.