The nucleoli are the site of the production of ribosomes, the protein synthetic apparatus of the cell. The presence of enlarged nucleoli, reflecting increased ribosomal gene transcription, has long been used by pathologists as an indicator of aggressive tumors. However, over the last 10 years a growing body of evidence has revealed that the nucleolus contains a dynamic cohort of over 4500 proteins, the majority of which have no function in ribosome production. The activity of some of these proteins is modulated by their regulated sequestration and release from the nucleolus. In particular, the nucleolus plays a central role in sensing cellular stress to modulate the abundance of the critical tumor suppressor protein p53. The finding that p53 activity is dysregulated in up to 50% of all human cancers highlights the importance of the nucleolar stress response in limiting malignant transformation. The development of drugs to selectively inhibit transcription of the ribosomal RNA genes in the nucleolus has paved the way for a new therapeutic approach to hijack nucleolar stress to selectively and non-genotoxically activate p53 in tumor cells. Here, we describe the potential application of this exciting new class of drugs for the treatment of human cancer.