Originally rising to notoriety for their function in regulating the aging, sirtuins are a group of NAD-dependent enzymes that are related to a steadily increasing some biological processes. In addition to controlling aging, sirtuins play key roles in maintaining the organism metabolic homeostasis. These enzymes have primarily preventative roles in the development of many age-related diseases, including cancer, neurodegeneration, and cardiovascular diseases. Seven isoforms of this enzyme have been specified in mammals, (SIRT1–7), all of them involve a conserved catalytic core and show differential subcellular localization and activities. Oxidative stress can affect the activity of sirtuins at different levels: expression, post-translational modifications, protein-protein interactions, and NAD levels. Mild oxidative stress induces the expression of sirtuins as a compensatory mechanism, while harsh or prolonged oxidant conditions result in dysfunctional modified sirtuins more prone to degradation by the proteases. Oxidative post-translational modifications have been identified in vitro and in vivo, in particular, cysteine oxidation and tyrosine nitration. Nevertheless, further studies are necessary to find out the molecular mechanisms of redox regulation of sirtuins to further design appropriate pharmacological interventions.