Rodent models for human diseases contribute significantly to understanding human physiology and pathophysiology. However, given the accelerating pace of drug development, there is a crucial need for in vivo preclinical models of human biology and pathology. The humanized mouse is one tool to bridge the gap between traditional animal models and the clinic. The development of immunodeficient mouse strains with high-level engraftment of normal and diseased human immune/hematopoietic cells has made in vivo functional characterization possible. As a patient-derived xenograft (PDX) model, humanized mice functionally correlate putative mechanisms with in vivo behavior and help to reveal pathogenic mechanisms. Combined with single-cell genomics, humanized mice can facilitate functional precision medicine such as risk stratification and individually optimized therapeutic approaches. New generations of humanized mice replicate much of the complexity and heterogeneity of both normal and malignant human hematopoiesis.Humanized mice allow in vivo characterization of the engraftment and differentiation capacities of hematopoietic stem/progenitor cell subpopulations, as well as the functional discrimination of normal and malignant stem cells.Humanized mice can support a functional correlation of genomic data with the in vivo characteristics of hematopoietic cells. Combined with single-cell genomics, the genetic heterogeneity within subpopulations of normal or malignant human hematopoietic cells can be linked to in vivo functions and can reveal pathogenetic mechanisms.