Reactive oxygen species (ROS) are important in regulating normal cellular processes, but deregulated ROS contribute to the development of various human diseases, including cancers. Cancer cells have increased ROS levels compared with normal cells, because of their accelerated metabolism. The high ROS levels in cancer cells, which distinguish them from normal cells, could be protumorigenic, but are also their Achilles' heel. The high ROS content in cancer cells renders them more susceptible to oxidative stress-induced cell death, and can be exploited for selective cancer therapy. In this review, we describe several potential therapeutic strategies that take advantage of ROS imbalance in cancer cells by further increasing oxidative stress, either alone or in combination with drugs that modulate certain signaling pathways. ©2013 AACR.