In 1987, a distinctive brain tumor arising in young children was first described. This tumor contained neuroepithelial, peripheral epithelial, and mesenchymal elements, but lacked divergent tissue differentiation characteristic of malignant teratomas. It was originally designated as atypical teratoid tumor, but because of the prominent rhabdoid component, the tumor designation was modified to atypical teratoid/rhabdoid tumors (AT/RT) of infancy and childhood. AT/RTs occur most commonly in infants under 2 years of age, often have central nervous system (CNS) dissemination, do not respond to therapy, and typically are fatal within 1 year. Most are located in the cerebellum (65%), but they may arise at any CNS site. Histologically, various patterns can be present within the same tumor, but they all have a population of rhabdoid cells, and 70% contain fields typical of a primitive neuroectodermal tumor (PNET/medulloblastoma). Less frequently, malignant mesenchymal tissue and/or an epithelial component are found. Necrosis and brisk mitotic activity are common. The immunocytochemical profile is complex, but germ cell markers are consistently negative. Ultrastructural features vary and depend on the site sampled, but whorled bundles of cytoplasmic intermediate filaments are a distinctive finding in cells of the rhabdoid component. The authors report 4 AT/RTs (2 males, 2 females, age range 6 months to 4 1/2 years, 3 cerebellar, 1 cerebral). All cases showed a variety of histologic patterns with necrosis. Typical rhabdoid cells, PNET areas, undifferentiated bland large cell regions, dense connective tissue, and solid clusters of epithelial cells were present. Immunocytochemistry showed strong vimentin reactivity, whereas epithelial membrane antigen, cytokeratin, glial fibrillary acidic protein, S-100 protein, desmin, and smooth muscle actin were present to a lesser extent in most cases. Germ cell markers were negative. Ultrastructurally, many cells contained aggregates of cytoplasmic intermediate filaments, and some cells had a basal lamina on one aspect. Cells with interdigitating cytoplasmic borders were seen and rare cells had microtubules. Cytogenetic studies were normal in 2 cases. Follow-up has shown that 3 children have died of disease (< 1 year after diagnosis) and 1 child is alive with disease (18 months after diagnosis). Separation of AT/RT from PNET based on histopathologic and biologic evaluation is important, because AT/RTs are aggressive tumors with a dismal prognosis and currently there is no effective treatment. Neither clinical signs and symptoms nor radiologic features will distinguish AT/RTs from PNETs.