The eukaryotic genome is prone to endogenous and environmental insults that constantly threaten an organism's genomic stability and survival. DNA damage and repair occur in the context of chromatin, where genomic DNA is highly organized and compacted around histone proteins. Although histones provide some level of protection against DNA damage, they also act as an accessibility barrier to DNA repair factors and consequently, the chromatin landscape must be ‘re-shaped’ to allow repair to occur. During this reshaping, histone posttranslational modifications, such as histone acetylation, play a critical role in regulating nucleosome dynamics and recruiting chromatin-modifying factors involved during base excision repair (BER) activities and preventing adverse consequences of DNA damage such as mutagenesis. One of these mechanisms is the action of the NAD⁺-dependent protein deacetylases, SIRT1 and SIRT6, that have been shown to target specific histone sites for deacetylation while also regulating the acetylation status of BER enzymes, affecting their cellular localization and enzymatic activities. This review provides a summary of exciting new information that has emerged on the role of SIRT1 and SIRT6 in regulating BER in the context of chromatin.