Wilms' tumor, a childhood malignancy of the kidney, is one of the most common pediatric tumors. The disease occurs in both sporadic and hereditary forms and is associated with a number of congenital disorders. Wilms' tumor appears to be genetically heterogeneous although only a single Wilms' tumor suppressor gene, designated WT1, has been isolated to date. WT1 encodes a zinc finger protein and is mutated in a subset of Wilms' tumors and in patients with Denys-Drash syndrome (DDS), an association of Wilms' tumor and severe genitourinary defects. This thesis reports a mutational analysis of WT1, detailing the spectrum and frequency of mutations in sporadic Wilms' tumors. Most WT1 mutations were homozygous and were predicted to cause premature termination of translation, suggesting that tumorigenesis associated with WT1 involves a two-hit mechanism. The mutational status of WT1 was determined in patients with variable expressivity of the DDS phenotype in order to assess potential genotype/phenotype correlations. Patients with less severe developmental anomalies had germline mutations predicted to result in truncated WT1 proteins, while those with full manifestation of DDS were characterized by missense mutations in the zinc finger region. This demonstrates that different mutations in WT1 are associated with specific effects on genitourinary development.