Human glial progenitor cells (hGPCs) can engraft, expand, and differentiate into functional oligodendrocytes and astrocytes when transplanted neonatally into murine hosts, in which they outcompete the host glial pool to ultimately colonize and dominate the recipient brains. When congenitally hypomyelinated mutants are used as hosts, the donor hGPCs generate myelinogenic oligodendrocytes as well as astrocytes, so that the recipient mice develop a largely humanized white matter, with entirely human-derived myelin. In addition, by neonatally engrafting hGPCs derived from patient- and disease-specific pluripotent stem cells, glial chimeric mice may be produced in which large proportions of all macroglial cells are not only human but also patient and disease specific. Human glial chimeric mice thus provide intriguing preparations by which to investigate the species-specific contributions of human glia to both cognition and human-selective neurodegenerative and neuropsychiatric diseases, as well as the potential for therapeutic glial cell replacement in these disorders. This review presents an overview of the uses, characteristics, and limitations of the human glial chimeric brain model, while providing a step-by-step protocol for the establishment of these mice.