Oxidative stress has long been linked to disease development and accelerated aging, prompting professionals in the biomedical field to suggest the use of antioxidants to prevent or even reverse these conditions. But growing clinical evidence is showing that this in fact might not be effective, calling for additional investigation to prove that certain molecular factors involved in oxidation, specifically reactive oxidative species (ROS), are not detrimental. In “Bedside to Bench,” Michael Ristow highlights recent human studies with antioxidant supplementation that have failed to show any improvement in health span. Moreover, other relevant evidence has pointed towards a beneficial role for ROS in lifespan under stress conditions, although how this is mediated and regulated inside the cell is not fully understood. In “Bench to Bedside,” Hiroyuki Kawagishi and Toren Finkel peruse the biological and signaling underpinnings of ROS in living organisms, which suggest different amounts of ROS may explain their dual role in lifespan and disease and the lack of effect of antioxidants in the body. The authors propose targeting pathways and molecules involved in removing cellular damage rather than ROS, which could make therapies to increase lifespan more effective and preclude diseases caused by oxidation and aging.