Human immunodeficiency virus (HIV) has infected millions of people worldwide and continues to be a major global health problem. Scientists required a small animal model to study HIV pathogenesis and immune responses. To this end, humanized mice were created by transplanting human cells and/or tissues into immunodeficient mice to reconstitute a human immune system. Thus, humanized mice have become a critical animal model for HIV researchers, but with some limitations. Current conventional humanized mice are prone to death by graft versus host disease induced by the mouse signal regulatory protein α and CD47 signaling pathway. In addition, commonly used humanized mice generate low levels of human cytokines required for robust myeloid and natural killer cell development and function. Here, we describe recent advances in humanization procedures and transgenic and knock-in immunodeficient mice to address these limitations.