Conventional myeloablative conditioning regimens prior to hematopoietic cell transplantation (HCT) are associated with significant transplant-related morbidity and mortality in children affected by primary immunodeficiency disorders. Reduced-intensity conditioning regimens have been extensively used without severe acute toxicity in patients with pre-HCT comorbidities, with the additional advantage of reducing or avoiding long-term sequelae such as infertility and growth retardation. Compared with myeloablative HCT, reduced-intensity conditioning regimens are associated with an increased incidence of mixed donor chimerism and graft rejection. While mixed donor engraftment is likely to correct the phenotypic expression of most children with primary immunodeficiency disorders, the use of donor lymphocyte infusion to increase donor chimerism or second HCT procedures may be required in some cases. Here we discuss the most recent data on the use of different reduced-intensity conditioning protocols in children with primary immunodeficiency disorders, highlighting significant clinical lessons and areas that need additional study.