The phytochemical resveratrol (RV) has become a focus of intense research owing to its roles in promoting longevity and in cancer prevention. As an anticancer agent, RV has primarily been linked to growth and death regulatory pathways. There is now growing evidence that, under physiological conditions, RV additionally contributes to the maintenance of genome stability. Thus, at the stage of DNA damage formation, RV protects the genome as an antioxidant via inhibition of inflammation, suppression of metabolic carcinogen activation, de novo expression of genes that encode detoxifying proteins and possibly even via radical scavenging properties. However, results demonstrating RV-dependent DNA breakage in the presence of Cu(II) ions and inhibition of DNA polymerases alpha and delta produced some controversy regarding RV's role as a caretaker compound. Significantly, recent studies have revealed that activation of ataxia telangiectasia mutated and ataxia telangiectasia Rad3 related could be a central effect of RV that underlies cell-cycle regulation and the newly described activation of fidelity control mechanisms in DNA double-strand break repair involving Nbs1 and p53. In this review, we discuss the existing data on RV's direct and indirect effects on genome integrity, in the light of future chemopreventive and chemotherapeutic protocols involving RV or related compounds.