Reactive Oxygen Species (ROS) management in cancer cells is important for developing successful therapy. Most of the anticancer agents induce ROS generation to kill cancer cells by apoptosis through common molecular pathways. But prolonged treatment with the drug reduces ROS level to confer resistance. Subsequently, drug resistant cells have lower ROS content than drug sensitive cancer cells. Anticancer drugs induce master regulatory genes and these genes act on NFE2L2-KEAP1 antioxidant system to reduce the ROS level in cancer cells. This review focused on the genetic mechanism of drug mediated induction of ROS generation in sensitive cells and the ROS reduction in drug resistant cancer cells.