Significant advances in the treatment of HIV infection have been made in the last three decades. Antiretroviral therapy (ART) is now potent enough to prevent virus replication and stop disease progression. However, ART alone does not cure the infection, primarily because HIV can persist in stable long-term reservoir cells including latently-infected CD4 + T cells. A central goal of the HIV research field is to devise strategies to eliminate these reservoirs and thereby develop a cure for HIV. This requires robust in vivo model systems to facilitate both the further characterization of persistent HIV reservoirs and evaluation of methods for eliminating latent virus. Humanized mice have proven to be versatile experimental models for studying many basic aspects of HIV biology. These models consist of immunodeficient mice transplanted with human cells or tissues, which allows development of a human immune system that supports robust infection with HIV. There are many potential applications for new generations of humanized mouse models in investigating HIV reservoirs and latency, but these models also involve caveats that are important to consider in experimental design and interpretation. This review briefly discusses some of the key strengths and limitations of humanized mouse models in HIV persistence studies.