Morphologic abnormalities of the nucleolus, the site of transcription of the ribosomal genes (rDNA) by RNA Polymerase I (Pol I), have been recognized as diagnostic for cancer for more then a century. Nevertheless, a critically unresolved question has been whether the accelerated ribosome biogenesis responsible for the nucleolar changes is required for maintenance of the malignant phenotype. Leveraging genetic manipulation and a novel selective small molecule inhibitor of Pol I transcription (CX-5461) we developed in collaboration with Cylene Pharmaceuticals (1), we provide the first definitive evidence that accelerated rDNA transcription and nucleolar integrity are necessary for oncogenic activity in hematologic tumour cells (2,3). Further, we show that Pol I transcription can be targeted in vivo to therapeutically treat tumors in both genetically engineered and xenograft models of lymphoma and leukemia through the non-genotoxic activation of p53-dependent apoptosis, while sparing normal cells of hematological lineages (2). Thus, selective inhibition of Pol transcription, a process previously considered to be a ‘”house keeping” process and undruggable, can serve as a novel therapeutic strategy for the treatment of cancer. Based on this data, in October 2012 the first clinical trial of CX-5461 in lymphoma and leukaemia patients will commence at Peter MacCallum Cancer Centre (G McArthur, S Harrison and R Hannan) in collaboration with Cylene Pharmaceuticals and funded in part through a NHMRC Development Grant. The trial will consist of a dose escalation phase and an expansion cohort at the maximum tolerated dose that will more robustly examine proof-of-mechanism and predictive biomarkers.