There are few models in which HIV pathogenesis, particularly gut-associated lymphoid tissue CD4+ T-cell depletion, can be studied and in which potential clinical interventions against HIV disease can be evaluated. HIV cannot be studied in normal mice due to the limited species tropism of the virus. Through the pioneering efforts of many investigators, humanized mice are now routinely used to rapidly advance HIV research. It is important to recognize that not all humanized murine models are equal, and their strengths and weaknesses must be taken into consideration to obtain information that is most relevant to the human condition. This review distinguishes the major humanization protocols and highlights each model’s recent contributions to HIV research, including mucosal transmission, gut-associated lymphoid tissue pathogenesis, and the evaluation of novel therapeutic and prevention approaches to potentially treat HIV disease and prevent the further spread of AIDS.