Allogeneic hematopoietic stem cell transplantation (HCT) is curative for many blood malignancies. This procedure balances the need for engraftment of donor cells while enhancing the curative graft-versus-tumor response. The need to diminish morbidity associated with HCT protocols has led to the development of reduced-intensity conditioning protocols. Modeling the clinical scenario that patients undergo in preclinical small animal models is challenging. We describe herein a mouse model using a conditioning regimen consisting of cytotoxic drugs similar to some human protocols together with reduced-intensity radiation. Furthermore, the choice of a major histocompatibility-matched, minor histocompatibility-mismatched C57BL/6 (H-2b) donor to BALB.b (H-2b) recipient strain combination resembles the allogeneic human leukocyte antigen-identical sibling or matched unrelated human transplant setting.