The transcriptional repressors of the Polycomb group (PcG), together with the counteracting Trithorax group (TrxG) proteins, establish a form of cellular memory by regulating gene expression in a heritable fashion at the level of chromatin. This cellular memory function is required for a correct cell fate/behavior, which is not only crucial during development for the generation of a correct body plan but also later in life to prevent cellular transformation. Here, we summarize the rapidly accumulating data that implicate several mammalian PcG members in the control of cellular proliferation and tumorigenesis.