Recent studies indicate a dual epigenetic role of the Polycomb group (PcG) proteins in self-renewal of stem cells and oncogenesis. Their elevation in our previous human kidney microarray screen led us examine whether they participate in processes involving normal and malignant renal progenitors. We therefore analyzed the expression of the PcG genes (EZH2, BMI-1, EED, SUZ12) in relation to that of the nephric-progenitor genes (WT1, PAX2, SALL1, SIX2, CITED1) using real-time polymerase chain reaction and methylation assays during renal development, regeneration, and tumorigenesis. Although all of the nephric-progenitor genes were shown to be developmentally regulated, analysis of polycomb gene expression during murine nephrogenesis and in an in vitro induction model of the nephrogenic mesenchyme indicated dynamic regulation only for EZH2 in the normal renal progenitor population. In contrast, induction of adult kidney regeneration by ischemia/reperfusion injury resulted primarily in rapid elevation of BMI-1, whereas EZH2 was silenced. Analysis of renal tumorigenesis in stem cell-like tumor xenografts established by serial passage of Wilms' tumor (WT) in immunodeficient mice showed cooperative upregulation of all PcG genes. This was accompanied by upregulation of WT1, PAX2, and SALL1 but downregulation of SIX2. Accordingly, methylation-specific quantitative polymerase chain reaction demonstrated promoter hypomethylation of WT1, PAX2, and SIX2 in primary WT and fetal kidneys, whereas progressive WT xenografts showed hypermethylation of SIX2, possibly leading to loss of renal differentiation. PcG genes vary in expression during renal development, regeneration, and tumorigenesis. We suggest a link between polycomb activation and epigenetic alterations of the renal progenitor population in initiation and progression of renal cancer.