Humanized mice, that is, animals engrafted with human tissues and/or expressing human genes, have been instrumental in improving our understanding of the pathogenesis and immunological processes that define some of the most challenging human-tropic viruses. In particular, mice engrafted with components of a human immune system (HIS) offer unprecedented opportunities for mechanistic studies of human immune responses to infection. Here, we provide a brief overview of the current panel of HIS mouse models available and cite recent examples of how such humanized animals have been used to study immune responses and pathogenesis elicited by human-tropic viruses. Finally, we will outline some of the challenges that lay ahead and strategies to improve and refine humanized mice with the goal of more accurately recapitulating human immune responses to viral infection.