Mammalian cells produce reactive oxygen species (ROS) which are carcinogens, key actors of the non-specific immune defense against pathogens and, in a more subtle way, of signal transduction, cellular metabolism and functions. Oxidative stress can induce severe damage to the host which in turn adapted to face oxidative injury. Disruption of redox balance leads to various pathological conditions, such as cancer. In this review we explore the network linking ROS, cancer cells, anti-tumor immunity and therapy. We emphasize recent findings regarding the oxidative tumor microenvironment and the correlation between ROS, proliferation and death of cancer cells. Further-on we highlight that granulocytes, as key inflammatory cells and ROS producers, are nowadays exploited for eradication of cancer cells. Finally, we focus on ROS-inducing anti-neoplastic therapies (radiotherapy and photodynamic therapy) and on controversial issues regarding the interference between chemotherapy, ROS and antioxidants. This review is directed mainly to researchers involved in anti-cancer drug development by pointing out that redox balance is a suitable therapeutic target, either alone or in combination with other pathways of cancer cells killing. We emphasize critical redoxcontrolled checkpoints that have to be taken into account in drug design for achieving good therapeutic efficiency and convenient side-effects.