Given the immense and growing cost of occupational stress to society through lost productivity and the burden to healthcare systems, current best practices for detecting, managing and reducing stress in the workplace are clearly sub-optimal and substantially better methods are required. Subjective, self-reported psychology and psychiatry-based instruments are prone to biases whereas current objective, biology-based measures produce conflicting results and are far from reliable. A multivariate approach to occupational stress research is required that reflects the broad, coordinated, physiological response to demands placed on the body by exposure to diverse occupational stressors. A literature review was conducted to determine the extent of application of the emerging multivariate technology of metabolomics to occupational stress research. Of 170 articles meeting the search criteria, three were identified that specifically studied occupational stressors using metabolomics. A further ten studies were not specifically occupational or were of indirect or peripheral relevance. The occupational studies, although limited in number highlight the technological challenges associated with the application of metabolomics to investigate occupational stress. They also demonstrate the utility to evaluate stress more comprehensively than univariate biomarker studies. The potential of this multivariate approach to enhance our understanding of occupational stress has yet to be established. This will require more studies with broader analytical coverage of the metabolome, longitudinal sampling, combination with experience sampling methods and comparison with psychometric models of occupational stress. Progress will likely involve combining multi-omic data into a holistic, systems biology approach to detecting, managing and reducing occupational stress and optimizing workplace performance.