Since the late 1980s, the study of the function and development of the human immune system has made intensive use of humanized animal models, among which mouse models have been proven extremely efficient and handy. Recent advances have lead to the establishment of new models with improved characteristics, both in terms of engraftment efficiency and in situ multilineage human hematopoietic development. In particular, the use of newborn BALB/c Rag2-/-gamma c-/- mice as recipients for human hematopoietic stem cells has proven particularly efficient. We describe here how to produce and monitor such "human immune system" (HIS) (BALB-Rag/gamma) mice, which offer large prospects for experimental study of the human immune system and as a preclinical screening tool.