There has been a robust discussion for many years now on the utility, or lack thereof, of mouse tumor xenograft models in the study of human cell and gene therapies. 1–4 Of course, the reality is that the value of a model depends on what the modeler is trying to accomplish. A good use of human tumor xenograft models would be to support an experimental hypothesis, a bad use would be to present animal data that add little to the value of in vitro data, and an ugly use of tumor xenografts would be to facilitate publication of a manuscript or give a false sense of safety or efficacy. The first use of inbred mouse strains for the propagation of human tumors was reported 50 years ago with the transplantation of human tumors into athymic “nude” mice. 5, 6 This was followed a decade later by the adoption of the severe combined immunodeficiency (SCID) mouse as the mainstay of tumor xenotransplantation work. 7, 8 Because the scid mutation (now called Prkdc) is leaky and does not negate the development of cells of the innate immune system, particularly natural killer cells, the SCID mouse cannot sustain complex xeno grafts involving human hematopoietic cells. In 1995, Shultz and colleagues8 utilized a cross of SCID mice with nonobese diabetic (NOD) mice to generate animals with defects in both the adaptive and innate immune systems; this facilitated hematopoietic cell engraftment, but these animals have some residual innate immune cell reactivity. Currently, many investigators use third-generation immunodeficient mice that combine the NOD-SCID mice with animals that have additional defects in the interleukin-2 receptor a-chain gene (IL2rg), also called the common a-chain gene (ac), and these animals are often referred to as NSG (NOD-scid-ac) mice (see ref. 4 for a review of the development of these mice). The successful clinical application of adoptive cell therapy for cancer, 9–11 along with the US Food and Drug Administration approval of the cellular vaccine sipuleucel-T and the immune checkpoint–blocking antibody ipilimumab, has led to an increased interest in immune-based anticancer therapies. In the context of human tumor xenotransplantation, when the innate and adaptive immune systems of the mouse have been eliminated, cell-based anticancer therapies can be thought of as add-back experiments. Two successful applications for which these mice have been used are in studying homeostatic expansion of various human T-cell subsets and in the development of “humanized” mice containing multiple cells and tissues of the human immune system. Human T cells come in multiple subtypes that are beyond the scope of this Commentary, and immunodeficient mice have been valuable for studies in which purified subsets are transplanted into these animals and the survival of various populations followed over time. For example, in a recent article by Gattinoni and colleagues, 12 a distinct subset of human CD8+ T cells with self-renewal and memory properties (stem cell–like memory T cells, Tscm cells) was demonstrated to reconstitute NSG mice with multiple effector cell lineages and could also be effectively used to transfer antitumor activity. It is also possible to add back multiple components of the human immune system to immunodeficient mice. Sometimes called BLT (bone marrow, liver, and thymus) mice, these animals are regenerated with fetal tissues and CD34+ hematopoietic progenitor cells to incorporate multiple components of the human immune system. 13–15 Although BLT mice are difficult to establish, they have been used with success in studies of pathogens that infect cells of the human immune system (eg, HIV), in which it has …