Flavonoids are secondary plant products that are well represented in healthy diets because of ingestion of fruit, vegetables, herbs, and teas. Increased consumption is correlated with decreased risks of cardiovascular disease, cancer, and other chronic diseases. Certain flavonoids confer direct antioxidant protection to cells, others induce enzymes that protect cells against oxidative and other insults ("indirect antioxidants"), and others appear to be protective by both mechanisms. Hydroxylated flavones manifest substantial direct antioxidant activity but do not effectively induce cytoprotective enzymes. Methoxylated flavones that potently induce cytoprotective enzymes were evaluated to elucidate the structural prerequisites for effective chemoprotective agents: protecting healthy cells with minimal collateral toxicity. Flavones and flavanones methoxylated at the 5-position of the A-ring were among the most potent inducers of the cytoprotective NAD(P)H:quinone-oxidoreductase 1 (NQO1) in 3 different cell lines. Other flavones were equally potent inducers, but more toxic. Flavanones contain no Michael reaction center, yet some are potent inducers of NQO1, have low cytotoxicity, and inhibit LPS-stimulated iNOS activity, which suggests a redox mechanism of action rather than the Keap1/Nrf2/ARE mechanism by which so many of the classic inducers operate. Evaluation in vivo will reveal whether differential protective advantages support their possible evaluation in a cancer prevention setting.