Advancements in new immuno-oncology therapeutics have necessitated comprehensive cell humanized mouse platforms that better support engraftment of human immune cell types such as T cells, B cells, myeloid cells, natural killer cells, and gamma delta T cells. Hematopoietic stem cell (HSC) and peripheral blood mononuclear cell (PBMC)-engrafted mouse models are distinct modalities that enable in vivo study of therapies that engage both human immune cells and human oncology-relevant targets. Immune cell and tumor humanized platforms enable evaluation of the preclinical efficacy and safety of new immuno-oncology therapeutics, leading to improved design and outcomes of clinical trials.