Studies of human immune cells and their role in defense against human tumor and human specific pathogens have largely been restricted to in vitro experiments which lack the complexity of whole organisms, or mouse models which differ significantly from humans. Humanized mouse model that support the development of human leukocytes are a promising avenue of research that aims to address this problem. We have recently examined immunodeficient mouse strains for their abilities to develop human innate and adaptive immune cells after transplantation of human umbilical cord blood stem cells. RAG2 (-/-) gammac (-/-) mouse strain with a BALB/c background and NOD/SCID- gammac (-/-) mouse strain were chosen as the most appropriate models and were then examined for their ability to mount innate and adaptive immune responses against human specific pathogens and tumor cells. We have used this model to study the function of human NK cells against human leukemia and breast cancer cells. In addition, we have studied the innate and adaptive immunity in the humanized mice against genital HSV-2 infection. More recently, we have shown, for the first time, that humanized mice are susceptible to S. typhi challenge and that this model can be utilized to study the pathogenesis of S. typhi to develop novel therapeutic strategies. Currently, we are investigating whether humanized mouse model can serve as an animal model for malaria infection. We and others have provided evidence that humanized mouse model can provide a mean for studying human immune responses in vivo using a small-animal model and may become an important preclinical tool to study human exclusive pathogens and cancer cells.