Somatic cells have approximately 200 hundred copies of ribosomal RNA (rRNA) genes (rDNA) per haploid genome of which only a fraction are transcribed by RNA polymerase I (Pol I) at any given time. Thus regulation of rDNA transcription involves controlling both the number of active genes as well as the rate of transcription per gene. How and why a majority of rDNA are silenced is unclear but recent studies indicate that in addition to controlling rRNA synthesis, rDNA silencing plays an essential role in maintaining the genetic stability of rDNA repeats and influences cellular events such as aging and senescence. In this review we discuss the role of the cytoarchitectural transcription factor UBF in determining and maintaining the active (euchromatic) state of rDNA in mammals. In particular we discuss evidence to suggest that UBF dynamically regulates the active rRNA gene pool during differentiation and malignancy.