Recent papers published in Nature by Guardavaccaro et al. and Westbrook et al. describe a nexus of two masters of negative regulation of protein levels. Both of these studies establish that the transcriptional repressor REST/NRSF is regulated by the highly versatile ubiquitin protein ligase (E3) SCF(beta-TrCP), adding a new dimension to the relationship between the ubiquitin-proteasome system and epigenetic regulation of transcription. These studies elucidate a critical means of regulation for REST, with implications for neuronal stem cell differentiation and the dual roles of this protein as a tumor suppressor and oncogene. These findings and their significance are discussed herein.