Our findings in the present study introduce Nrf2 activation as a resistance factor against HDACi, suggesting the possibility of a stratified treatment approach: Tumors with defective Nrf2 regulation may show a higher sensitivity to HDACi than tumors with normal Nrf2 function, while, vice versa, cancer cells with constitutively active Nrf2 may have a lower susceptibility to HDACi, thus requiring Nrf2 inhibition or knockdown for enhancing HDACi efficacy. This evidence concerns the gene NFE2L2 and cancer.