ABSTRACT The biological effects of oxidants, especially reactive oxygen species (ROS), include signaling functions (oxidative eustress), initiation of measures to reduce elevated ROS (oxidative stress), and a cascade of pathophysiological events that accompany excessive ROS (oxidative distress). Although these effects have long been studied in animal models with perturbed ROS, their actions under physiological conditions are less clear. I propose that some of the apparent uncertainty may be due to confusion of ROS with endogenously generated reactive sulfur species (RSS). ROS and RSS are chemically similar, but RSS are more reactive and versatile, and can be stored and reused. Both ROS and RSS signal via oxidation reactions with protein cysteine sulfur and they produce identical effector responses, but RSS appear to be more effective. RSS in the form of persulfidated cysteines (Cys-S-S) are produced endogenously and co-translationally introduced into proteins, and there is increasing evidence that many cellular proteins are persulfidated. A number of practical factors have contributed to confusion between ROS and RSS, and these are discussed herein. Furthermore, essentially all endogenous antioxidant enzymes appeared shortly after life began, some 3.8 billion years ago, when RSS metabolism dominated evolution. This was long before the rise in ROS, 600 million years ago, and I propose that these same enzymes, with only minor modifications, still effectively metabolize RSS in extant organisms. I am not suggesting that all ROS are RSS; however, I believe that the relative importance of ROS and RSS in biological systems needs further consideration.