Clear-cell renal cell carcinoma (ccRCC; depicted in the background) is characterized by inactivation of the VHL tumor suppressor gene with consequent upregulation of HIF and HIF target genes (shown in the microarray). One such gene is REDD1, which is consistently upregulated in ccRCC, but which inhibits mTORC1. This creates a paradox, however, as mTORC1 is commonly found to be active in ccRCC. One mechanism whereby mTORC1 becomes uncoupled from REDD1 is through REDD1 mutation (as shown in the chromatogram). For further details, please see Kucejova and coworkers on page 1255 in this issue.