The term “stress” is used to capture important phenomena at multiple levels of biological organization, but finding a general and rigorous definition of the concept has provenchallenging. Current models in the behavioral literature emphasize the cognitive aspects of stress, which is said to occur when threats to the organism are perceived as uncontrollable and/or unpredictable. Here we adopt the perspective of systems biology and take a step toward a general definition of stress by unpacking the concept in light of control theory. Our goal is to clarify the concept so as to facilitate integrative research and formal analysis. We argue that stress occurs when a biological control system detects a failure to control a fitness-critical variable, which may be either internal or external to the organism. Biological control systems typically include both feedback (reactive, compensatory) and feedforward (predictive, anticipatory) components; their interplay accounts for the complex phenomenology of stress in living organisms. The simple and abstract definition we propose applies to animals, plants, and single cells, highlighting connections across levels of organization. In the final section of the paper we explore some extensions of our approach and suggest directions for future research. Specifically, we discuss the classic concepts of conditioning and hormesis and review relevant work on cellular stress responses; show how control theory suggests the existence of fundamental trade-offs in the design of stress responses; and point to potential insights into the effects of novel environmental conditions, including those resulting from anthropogenic change.
