Theetiology of Wilms tumor, an embryonic kidney tumor, is genetically heterogeneous. One Wilms tumor gene, WT1,which encodes a zinc finger transcription factor, is mutated in 10–20% of Wilms tumors, but it is still not clear what critical cellular pathway(s) is affected by these mutations. Recently β-catenin mutations have been reported in 6 of 40 (15%) of Wilms tumors. β-catenin is the central effector in the Wnt signal transduction pathway, and deregulation of β-catenin signaling is critical in the development of a number of malignancies. The observation of β-catenin mutations in Wilms tumors suggests that abrogation of the Wnt signaling pathway also plays a role in some Wilms tumors. To assess the relationship of WT1 mutations vis-à-visβ-catenin mutations in Wilms tumor, we analyzed 153 primary tumors, and 21 of 153 (14%) carried β-cateninmutations. Surprisingly, we observed a highly significant(P = 3.6 × 10⁻¹³) association between WT1 and β-catenin mutations; 19 of 20 β-catenin-mutant tumors had also sustained WT1 mutations. By analogy to the patterns of concordant and discordant gene mutations observed in other tumors, our data suggest that mutation of WT1 and β-catenin affects two different cellular pathways,both of which are critically altered in at least a subset of Wilms tumors.