Although biological systems are more complex and can actively respond to their environment, an effective entry point to the development of a universal theory of biological stress is the physical concepts of stress and strain. If you apply stress to the end of a beam of steel, the strain will accumulate within that steel beam. If the stress is weak then the strain will disappear when the force is removed and the beam will return to its original state of form and functionality. If the stress is more severe, then the strain becomes permanent and the beam will be deformed, potentially losing some degree of functionality. In extremely stressful situations, the beam will break and lose most or all of its original functional capabilities. Although this stress-strain theory applies to the abiotic, stress and strain are also rules of life and directly relate to the form and function of living organisms. The main difference is that life can react and adjust to stress and strain to maintain homeostasis within a range of limits. Here, we summarize the rules of stress and strain in living systems ranging from microbes to multicellular organisms to ecosystems with the goal to identify common features that may underlie a universal biological theory of stress. We then propose to establish a range of experimental, observational, and analytical approaches to study stress across scales, including synthetic microbial communities that mimic many of the essential characteristics of living systems, thereby enabling a universal theory of biological stress to be experimentally validated without the constraints of timescales, ethics, or cost found when studying other species or scales of life. Although the range of terminology, theory, and methodology used to study stress and strain across the scales of life presents a formidable challenge to creating a universal theory of biological stress, working toward such a theory that informs our understanding of the simultaneous and interconnected unicellular, multicellular, organismal, and ecosystem stress responses is critical as it will improve our ability to predict how living systems respond to change, thus informing solutions to current and future environmental and human health challenges.