Most Wilms' tumors contain several predominant cell types, of which a primitive blastemal population is often the most prominent. Other typical components include undifferentiated mesenchymal and epithelial cells, but it has not been demonstrated that these components are neoplastic. We used a combined cytogenetic and fluorescence in situ hybridization approach to determine the clonal relationship of different cell populations within six Wilms' tumors. Clonal numerical chromosome aberrations in three Wilms' tumors were found in blastemal cells, but not in mesenchymal cells. Loss of one WT1 allele in two other tumors was detected in both blastemal and mesenchymal cells. Tetrasomy 18 in a sixth case was observed in mesenchymal and epithelial cells; blastemal cells could not be evaluated in this tumor. These findings demonstrate that mesenchymal and epithelial cells in some Wilms' tumors are neoplastic. Different histologic components in some Wilms' tumors derive from a single chromosomally aberrant ancestor which is most likely to be the primitive blastemal cell.