A quintessential trait of stem cells is embedded in their ability to self-renew without incurring DNA damage as a result of genome replication. One key self-renewal factor is the nucleolar GTP-binding protein nucleostemin (also known as guanine-nucleotide-binding protein-like 3, GNL3, in invertebrate species). Several studies have recently pointed to an unexpected role of nucleostemin in safeguarding the genome integrity of stem and cancer cells. Since its discovery, the predominant presence of nucleostemin in the nucleolus has led to the notion that it might function in the card-carrying event of the nucleolus – the biogenesis of ribosomes. As tantalizing as this might be, a ribosomal role of nucleostemin is refuted by evidence from recent studies, which argues that nucleostemin depletion triggers a primary event of DNA damage in S phase cells that then leads to ribosomal perturbation. Furthermore, there have been conflicting reports regarding the p53 dependency of nucleostemin activity and the cell cycle arrest profile of nucleostemin-depleted cells. In this Commentary, I propose a model that explains how the many contradictory observations surrounding nucleostemin can be reconciled and suggest that this protein might not be as multi-tasking as has been previously perceived. The story of nucleostemin highlights the complexity of the underlying molecular events associated with the appearance of any cell biological phenotype and also signifies a new understanding of the genome maintenance program in stem cells.