Theoretical models are needed to identify the adverse health aspects of stressful psychosocial work environments. One such model, the effort–reward imbalance model, has been widely analyzed in different occupations and different countries. This contribution briefly reviews the theoretical bases of this model, its measurement, and the available evidence on adverse health effects derived from prospective epidemiologic studies. Against this background, new conceptual and methodological challenges are discussed that result from economic globalization, in particular a globalized labor market. It is concluded that meeting these challenges will improve the usefulness of the model in predicting health and in strengthening work-related interventions globally.