Abstract Genetic mouse models have been a powerful system to delineate key mechanisms of cancer development. However, there are likely to be gene expression and regulation differences between mouse and man that affect the applicability of some findings in these models. Furthermore, the inbred strains that are used may come with additional genetic caveats due to loss of heterozygosity. For these and other reasons, many cancer studies that identify targets or mechanisms in mouse systems benefit from replicating key findings in a relevant human cell model. Indeed, this has become a common expectation for high impact studies. Human pediatric leukemia is genetically diverse with many potential combinations of driver and accessory mutations, each potentially affecting phenotype. Therefore, a large bank of xenograft models is required to replicate the heterogenous nature of the disease as found in patients. Xenograft technology continues to advance rapidly. There has been a steady proliferation of immunodeficient mouse strains, each with specific strengths relative to each other. More sophisticated in vivo studies are now possible because of these new strains and many other technical advances in sample processing, detection, analysis, and modeling of therapeutic interventions. However, these mice are difficult to breed and manipulate due to their immunodeficient status. Human cells also require a different set of considerations. Human hematopoiesis in this environment is very different from what is found in mouse transplant systems. There are additional host versus graft and graft versus host issues to consider. Human cells require different culture conditions and transduction protocols. Human cells are morphologically distinct. The markers used for detection are very different, making flow cytometry experiments much more involved. I have spent the last 19 years working with these models and have made continuous improvements along the way. I have a well-documented history of developing new innovative methods and models for the leukemia research community. My ability to apply my unique experiences to the projects of many NCI funded investigators through the set of xenograft resources that I have built adds significant efficiency and value to the science that can be done at our institution. This proposal is aligned with NCI initiatives to use mouse models and genomics to identify new molecular mechanisms of carcinogenesis, delineate mechanisms of resistance, and identify new targets for drug discovery and development.