Compelling evidence suggests that cancer cells are generally under reactive oxygen species (ROS) stress.As mitochondria respiration is the main source of ROS generation in the cells, MnSOD is of prime importance in maintaining the tumor cellular ROS balance.It has recently been reported that generation of ROS is closely involved in PPAR ligand-induced apoptosis.However, the mechanism by which these ligands induce ROS generation remains unknown.We report the identification of human MnSOD as a PPAR target gene and that activation by PPAR agonists led to downregulation of MnSOD gene expression in vitro and in vivo xenograft model.Futhermore, histopathologic analysis of breast cancer biopsies obtained from patients treated with synthetic PPAR agonists also showed MnSOD repression.Repression of MnSOD expression was accompanied with increase in intracellular superoxide production in breast cancer cells.Suppression of MnSOD levels by small-interfering RNA or activation of PPAR in breast cancer cells increased oxidative stress and enhanced chemo-sensitivity to ROS-inducing drugs such as docetaxel and doxorubicin.Importantly, normal breast cells were completely refractory to these effects.Together, our data not only identifies MnSOD as a novel PPAR target but also provides a molecular mechanism for ROS-manipulation therapy through the intelligent use of PPAR ligands in combination with ROS-inducing drugs to preferentially kill cancer cells.