The Wilms tumor 1 (WT1) gene encodes a transcription factor that was among the first tumor suppressor genes to be identified. Dependent on the splice variant, some WT1 isoforms can function as transcriptional regulators, whereas other WT1 proteins are presumably involved in RNA processing. The mechanisms by which WT1 regulates transcription and the identification of bona fide target genes have been difficult to study, which is partially due to the complex nature of the gene and its context specific functions. While the role of WT1 as a tumor suppressor in Wilms tumor is widely accepted, considerable evidence points to an oncogenic function in other tumors. Recent studies have provided new insights into the underlying mechanisms that lead to the development of Wilms tumor. In addition, a conditional Wt1 knockout mouse model and RNAi-mediated screening approaches have uncovered new functions for WT1 in development and tumorigenesis.