The study of human hematopoiesis is conditioned by access to nondiseased human tissue samples that harbor the cellular substrates for this developmental process. Technical and ethical concerns limit the availability to tissues derived from the fetal and newborn periods, while adult samples are generally restricted to peripheral blood. Access to a small animal model that faithfully recapitulates the process of human hematopoiesis would provide an important tool. Natural killer (NK) cells comprise between 10% and 15% of human peripheral blood lymphocytes and appear conserved in several species. NK cells are implicated in the recognition of pathogen-infected cells and in the clearance of certain tumor cells. In this chapter, we discuss NK cell developmental pathways and the use of humanized murine models for the study of human hematopoiesis and, in particular, human NK cell development.