The new-generation humanized (Hu) mouse models permit multilineage human hematopoiesis and generate T cells, B cells, macrophages, and dendritic cells required for a coordinated human immune response. Therefore, any desired antigen or human-specific pathogens that can infect humanized mice can be used to generate human antibody responses. Two leading humanized mouse models are currently being used. The Hu-HSC model uses the transplantation of human hematopoietic stem cells (HSCs), whereas the BLT mouse model is created by transplantation of human fetal liver, thymus, and HSC. A number of human pathogens such as HIV-1, dengue, Epstein-Barr virus, and hepatitis C virus have been studied in these systems. Responder antigen-specific B cells from these animals can be collected and used to generate human monoclonals by B-cell immortalization or by single-cell PCR methods to “rescue” antibody-producing genes for ectopic expression. Both models generate cellular and humoral immune responses. However, the antibodies generated are primarily of the IgM type because of the inefficient immunoglobulin class switch resulting in the suboptimal production of antigen-specific affinity-matured IgG. The current Hu mouse models thus far have permitted the analysis of human “antibodyome,” and recent reports demonstrated their utility in generating human monoclonal antibodies. Ongoing efforts at further refinements are expected to make these systems more efficient in the near future.