"Nothing in biology makes sense except in the light of evolution" (Theodosius Dobzhansky) and "For such a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied" (August Krogh); dictums that can be used to illustrate the past and provide a guide to the future. Although sulfur was integral in the origin of life, and nearly seven-eights of subsequent evolution, its physiological importance is largely overlooked because much of contemporary life it is based on oxygen and the adherent problems associated with oxygen deficit (hypoxia) or excess (oxidative stress). This graphical review will summarize sulfur's role in evolution and make a case that many of the regulatory activities attributed to oxygen and reactive oxygen species (ROS) can also be ascribed to reactive sulfur species (RSS). ROS and RSS are chemically similar and signal via identical cysteine residues on regulatory proteins and have identical downstream effector responses. Antioxidant mechanisms, generally attributed to the advent of an oxic existence, actually appeared over 2 billion years prior, in sulfur metabolizing organisms. Recent evidence suggests they are active in sulfur metabolism to this day. Understanding these aspects of ROS and RSS suggests that alternative mechanisms for oxidant/antioxidant pathways and therapies must be considered. As oxygen and reduced sulfur do not coexist, either in cells or the environment, it is also important to design and conduct experiments in oxygen levels that are physiologically relevant. For every experiment there are optimal conditions under which it must be studied. Copyright © 2020 Elsevier Inc. All rights reserved.