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Iron imbalance plays a pivotal role in oxidative damages associated with a wide range of pathological conditions. However, owing to the essential role of iron in biological processes, the beneficial effects of iron chelation therapy against oxidative damage have to be balanced against potential toxicity. The present review briefly introduces iron redox biochemistry and oxidative-stress associated pathologies, surveys recent advances in iron chelating strategies and summarizes some of our recent findings in this field, with a special emphasis on the chemical design constraints one must satisfy in order to synthesize iron chelators which could be beneficial against oxidative stress without inducing iron depletion of the body. The concept of oxidative stress activatable iron chelators is presented as a new paradigm for safe and efficient treatment of oxidative-stress associated conditions.