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In the current issue, Johnson and colleagues present exciting results, using biomarkers involved in aflatoxin B-1 (AFB(1))-induced hepatocarcinogenesis, as an example of a conceptual framework to target mechanisms of action in developing chemopreventive agents. Their innovative approach offers considerable promise for a field that has long been neglected. Proof-of-principle was demonstrated using a synthetic triterpenoid (CDDO-Im), which activates Nrf2 signal transduction pathway, inhibits formation of AFB(1)-induced DNA adducts and neoplastic hepatic foci, and alters the expression of genes associated with aflatoxin-mediated toxicity. (C) 2014 AACR.