The last segment of the 20th century primarily focused on understanding the mechanisms of programmed cell death as opposed to unprogrammed cell death, whereas the beginning of the 21st century is more-or-less involved in defining ways to maneuver programmed cell death in order to understand disease sequel. In this arena, phytochemicals appear to play an instrumental role in modulating various forms of cell death. Among thousands of phytochemicals investigated so far, the citrus flavonoid rutin (RUT) and Curcuma longa flavonoid curcumin (CUR) have captured the most attention due to their remarkable anticancer properties. Although curcumin has already gone into anticancer clinical trial, antitoxic properties of either CUR or RUT remain unknown to date. This study explored whether preexposure to CUR (17 mg/kg, p.o. for 12 days) and RUT (1.25 mg/kg orally for 14 days) has the potential to prevent acetaminophen (AP)-induced liver injury and apoptotic and necrotic cell deaths in vivo. Additional objectives were to determine whether exposure to these flavonoids modulates the expression of the anti-apoptotic gene bcl-XL, by influencing oxidative stress and genomic DNA fragmentation - the prime suspects responsible for turning on various forms of cell death. Male ICR mice were administered either CUR or RUT for 12 or 14 days followed by a highly hepatotoxic dose of AP (400 mg/kg, i.p.) for 24 hours. Serum and liver samples were collected and subjected to various analyses. The results indicated that CUR and RUT pre-exposures showed dramatic prevention against AP-induced liver injury by minimizing toxicant-induced oxidative stress and genomic DNA fragmentation which are instrumental in orchestrating apoptotic (programmed) and necrotic (unprogrammed) cell deaths in the liver. Western blot analysis disclosed the ability of CUR and RUT to block AP-induced decrease in bcl-XL expression. Overall, this study suggests that pre-exposure to CUR and RUT may prevent drug/chemicalIinduced organ injuries.