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Resveratrol, a polyphenolic compound found in grapes, has been shown to partially exert its anti-cancer function through the modulation of epigenetic events. However, the epigenetic targets of resveratrol in breast cancer are not yet fully understood. Here, we identified that the gene encoding the histone H2B ubiquitin ligase RNF20 (ring finger protein 20), a chromatin modifying enzyme and putative tumour suppressor, is up-regulated by resveratrol in MDA-MB-231 breast cancer cells. Up-regulation of RNF20 is achieved through an increase of active histone marks around its promoter. The increase in RNF20 in MDA-MB-231 likely contributes to p21 regulation and the anti-growth effects of resveratrol, as RNF20 knockdown diminished these effects. Our findings suggest that RNF20 is a novel epigenetic target of resveratrol, and increase our understanding of how it contributes to the chemopreventive effect of resveratrol in a more aggressive breast cancer cell line, MDA-MB-231.