Reactive oxygen species (ROS) act as a second messenger in cell signaling and are essential for various biological processes in normal cells. Any aberrance in redox balance may relate to human pathogenesis including cancers. Since ROS are usually increased in cancer cells due to oncogene activation, relative lack of blood supply or other variances and ROS do involve in initiation, progression and metastasis of cancers, ROS are considered oncogenic. Ironically, ROS production is a mechanism shared by all non-surgical therapeutic approaches for cancers, including chemotherapy, radiotherapy and photodynamic therapy, due to their implication in triggering cell death, therefore ROS are also used to kill cancer cells. Because of the double-edged sword property of ROS in determining cell fate, both pro- or anti-oxidant therapies have been proposed for treatments of cancers. Based on either side, a number of drugs, agents and approaches are developed or in the progress of development, some of which have shown clinical promise. This review summarizes the current understanding on ROS-manipulation strategies in cancer treatment and underlying mechanisms. ROS-producing or -eliminating agents and the potential drugs in this aspect are categorized. An effort is made in particular to discuss the paradox in the rationales of two opposite ROS-manipulation strategies and the concerns for their use. Selectivity between tumor and non-tumor cells may depend on difference of their redox environments. A combinational set of cellular parameters including redox status, antioxidant enzymes expression, cell signaling and transcription factor activation profiles, namely "redox signaling signature", is waiting for being developed in order to choose ROS-elevating or ROS-depleting therapy specific to certain type of cancer cells. In clinical setting individualized choice of an optimal ROS-manipulation therapy may require accurate and convenient measurements for ROS as well as "redox signaling signature" for prediction of efficacy and systemic toxicity.