Humanized mice, which we define as immunodeficient mice that have been reconstituted with a human immune system, represent promising preclinical models for translational research and precision medicine as they allow modeling and therapy of human diseases in vivo. The first generation of humanized mice showed insufficient development, diversity and function of human immune cells, in particular human natural killer (NK) cells and type 1 innate lymphoid cells (ILC1). This limited the applicability of humanized mice for studying ILC1 and NK cells in the context of human cancers and immunotherapeutic manipulation. However, since 2014, several next-generation humanized mouse models have been developed that express human IL-15 either as a transgene or knock-in (NOG-IL15, NSG-IL15, NSG-IL7-IL15, SRG-15) or show improved development of human myeloid cells, which express human IL-15 and thereby promote human NK cell development (NSG-SGM3, MISTRG, BRGSF). Here we compare the various next-generation humanized mouse models and describe the methodological procedures for creating mice with a functioning human immune system and how they can be used to study and manipulate human NK cells in health and disease.