Chronic inflammation is associated with a wide range of diseases, including cardiovascular diseases, cancer, diabetes, Alzheimer’s disease, pulmonary diseases, and autoimmune diseases [1]. Inflammation is normally a defensive immune strategy in response to infection or tissue injury that subsides again once the potential danger has been eliminated. However, in chronic inflammation the inflammatory response continues and can cause extensive damage to host tissue [2]. A major issue of treating many inflammation-related diseases including cancer is the lack of drug selectivity [3]. Consequently, treatment is often associated with severe adverse effects in healthy tissue. One strategy to increase efficacy of drugs and reduce toxic side effects is the development of tissue targeting prodrugs. A prodrug is an inactive form of a drug that becomes activated by chemical and/or enzymatic transformation in vivo. Typically, prodrugs are introduced to improve poor ADME properties, however, the prodrug strategy can also be exploited for site-selective drug delivery [4]. A distinctive feature of inflammation, to be targeted with such a strategy, is the significant increase in concentration of reactive oxygen species (ROS) that are produced by immune cells to combat invading pathogens [2]. In this work, we propose the use of ROS sensitive prodrugs for improved treatment of inflammatory disorders. See Figure 1. Based on a previously reported ROS labile promoiety, ROS sensitive prodrugs of existing drugs were designed and synthesized. In vitro testing of ROS activation and activity in cell-based assays have shown promising results. Furthermore, the prodrugs have shown good in vitro stability under various physiological conditions. Based on these preliminary results, this proposed ROS prodrug strategy shows great potential in improving the treatment of various inflammatory disorders including cancer. [1] Aggarwal, B. B., Shishodia, S., Sandur, S. K., Pandey, M. K. & Sethi, G. Inflammation and cancer: How hot is the link? Biochem. Pharmacol. 72, 1605–1621 (2006). [2] Mittal, M., Siddiqui, M. R., Tran, K., Reddy, S. P. & Malik, A. B. Reactive oxygen species in inflammation and tissue injury. Antioxid. Redox Signal. 20, 1126–67 (2014). [3] Zawilska, J. B., Wojcieszak, J. & Olejniczak, A. B. Prodrugs: A challenge for the drug development. Pharmacol. Reports 65, 1–14 (2013). [4] Rautio, J. et al. Prodrugs: design and clinical applications. Nat. Rev. Drug Discov. 7, 255–270 (2008).