There is a rebirth of humanized mouse models in reflecting human immunodeficiency virus (HIV) pathobiology. This has allowed new investigations of viral diversity, immunity and developmental therapeutics. In the past, HIV infection and disease were, in part, mirrored in immune deficient mice reconstituted with human hematopoietic stem cells. What remained from early studies reflected the ability to mirror central nervous system (CNS) disease. As the wide spread use of combination antiretroviral therapies has changed the severity, but not prevalence, of HIV-associated neurocognitive disorders (HAND), mimicking such virus-induced CNS morbidities in humanized animals is essential for HIV/AIDS research activities. To this end, we now review the evidence for how and under what circumstances humanized mice may be utilized for studies of HIV-1 neuropathogenesis.