The combined study of C and O isotopes in plant organic matter has emerged as a powerful tool for understanding plant functional response to environmental change. The approach relies on established relationships between leaf gas exchange and isotopic fractionation to derive a series of model scenarios that can be used to draw inferences about changes in photosynthetic assimi-lation and stomatal conductance driven by changes in environmental parameters (CO2, water availability, air humidity, temperature, nutrients). We review the mechanistic basis for model and research to date, and discuss where isotopic observations don’t match our current under-standing of plant physiological response to environment. We demonstrate that 1) the model has been applied successfully in many, but not all studies, and 2), while originally conceived for leaf isotopes, the model has been applied extensively to tree ring isotopes in the context of tree phys-iology and dendrochronology. Where isotopic observations deviate from physiologically plau-sible conclusions, this mismatch between gas-exchange and isotope response provides valuable insights on underlying physiological processes. Overall, we found that isotope responses can be grouped into situations of increasing resource limitation versus higher resource availability. Thus, the dual isotope model helps to interpret plant responses to a multitude of environmental factors.