Nucleostemin (NS) is a protein concentrated in the nucleolus of most stem cells and also in many tumor cells, which has been implicated in cell-cycle progression owing to its ability to modulate p53. Depletion of NS causes G(1) cell-cycle arrest, but its overexpression does so as well. Recently, this paradox has been clarified. NS overexpression causes a sequestration of murine double minute 2 (MDM2), preventing the destruction of p53. A recent study has demonstrated that loss of NS promotes the interaction of L5 and L11 ribosomal proteins with MDM2 and, thus, also prevents p53 degradation. This new finding expands our understanding of the multiple modes of NS action and reinforces the concept that the nucleolus has key roles in cell-cycle progression.