Previously, we found that Rb can actively repress transcription of cell cycle genes by binding and inactivating transcription factors at the promoter. Here, we demonstrate that Rb can also repress transcription of endogenous cell cycle genes containing E2F sites through recruitment of histone deacetylase, which deacetylates histones on the promoter, thereby promoting formation of nucleosomes that inhibit transcription. These two mechanisms of repression by Rb are selective—some promoters and transcription factors are blocked by this recruitment of histone deacetylase, whereas others are resistant to histone deacetylase activity and are repressed directly by inhibition of transcription factors.