There is a growing need for effective animal models to carry out experimental studies on human hematopoietic and immune systems without putting individuals at risk. Progress in development of small animal models for the in vivo investigation of human hematopoiesis and immunity has seen three major breakthroughs over the last three decades. First, CB 17-Prkdc(scid) (abbreviated CB 17-scid) mice were discovered in 1983, and engraftment of these mice with human fetal tissues (SCID-Hu model) and peripheral blood mononuclear cells (Hu-PBL-SCID model) was reported in 1988. Second, NOD-scid mice were developed and their enhanced ability to engraft with human hematolymphoid tissues as compared with CB17-scid mice was reported in 1995. NOD-scid mice have been the "gold standard" for studies of human hematolymphoid engraftment in small animal models over the last 10 years. Third, immunodeficient mice bearing a targeted mutation in the IL-2 receptor common gamma chain (IL2rgamma(null)) were developed independently by four groups between 2002 and 2005, and a major increase in the engraftment and function of human hematolymphoid cells as compared with NOD-scid mice has been reported. These new strains of immunodeficient IL2rgamma(null) mice are now being used for studies in human hematopoiesis, innate and adaptive immunity, autoimmunity, infectious diseases, cancer biology, and regenerative medicine. In this chapter, we discuss the current state of development of these strains of mice, the remaining deficiencies, and how approaches used to increase the engraftment and function of human hematolymphoid cells in CB 17-scid mice and in previous models based on NOD-scid mice may enhance human hematolymphoid engraftment and function in NOD-scid IL2rgamma(null) mice.