Publisher Summary Wilms' tumor presents a genetic pattern that may be intermediate in complexity, between the single-locus disease exemplified by retinoblastoma and the multistep tumorigenesis model proposed for colon cancer and other adult tumor types. It constitutes 10% of all pediatric cancers and is the most common intra-abdominal solid tumor in children. It can present a common sporadic and a rare hereditary form, along with various congenital abnormalities. The existence of both gross chromosomal abnormalities as well as more subtle molecular deletions has led to the genetic characterization of a number of loci involved in the development of Wilms' tumor. This chapter discusses the complex genetics of Wilms' tumor and the initial studies characterizing the role of the WT1 gene product in tumorigenesis. Wilms' tumor is very sensitive to chemotherapy. The genetic events underlying the development of Wilms' tumor are complex and the isolation of the WT1 gene has provided an initial molecular key to decipher this process. In Wilms' tumor, the prophetic model that Knudson and Strong had proposed based on epidemiologic analyses has stood the test of time and continues to provide a unifying theme for the molecular study of human neoplasia.