The role of sirtuins in cancer has recently stimulated both considerable interest and debate. It is becoming clear that some sirtuins deacetylate important tumor suppressors thereby impinging on their activity. Human SirT1, for instance, has been shown to deacetylate p53 in biochemical assays, and growing evidence indicates that it also performs this activity in cells. Since deacetylation of p53 correlates with a decreased p53 transcriptional function, it is conceivable that sirtuin inhibition could lead to improved tumor suppression. There are, however, still many open questions regarding, for example, whether sirtuins deacetylate those lysine residues in p53 that are critical for its activity. Preliminary observations also suggest that sirtuin-mediated modulation of p53 can also take place indirectly through changes in cellular processes (e.g., nucleolar function and p300 activity) known to affect p53. It also remains unclear whether depletion in the activity of a single sirtuin suffices to stabilize and activate p53 substantially or additional changes in other factors (including other sirtuins) are required. Finally, data from SIRT1-knockout mice demonstrate that sustained depletion of SirT1 can give rise to genomic instability and that, therefore, SirT1 acts as a tumor suppressor. This observation implies that the safety of therapeutic interventions based on SirT1 inhibition need to be evaluated. Here we review and examine the available data on the regulation of p53 by sirtuins and on the changes in sirtuin function in tumor cells, and discuss whether pharmacological inhibition of sirtuin activity constitutes an adequate approach for cancer treatment.