Objectives Contemporary research on the exposome, i.e. the sum of all the exposures an individual encounters throughout life and that may influence human health, bears the promise of an integrative and policy-relevant research on the effect of environment on health. Critical analyses of the first generation of exposome projects have voiced concerns over their actual breadth of inclusion of environmental factors and a related risk of molecularization of public health issues. The emergence of the European Human Exposome Network (EHEN) provides an opportunity to better situate the ambitions and priorities of the exposome approach on the basis of new and ongoing research. Methods We assess the promises, methods, and limitations of the EHEN, as a case study of the second generation of exposome research. A critical textual analysis of profile articles from each of the projects involved in EHEN, published in Environmental Epidemiology, was carried out to derive common priorities, innovations, methodological and conceptual choices across EHEN and to discuss it. Results EHEN consolidates its integrative outlook by reinforcing the volume and variety of data, its data analysis infrastructure and by diversifying its strategies to deliver actionable knowledge. Yet data-driven limitations severely restrict the geographical and political scope of this knowledge to health issues primarily related to urban setups, which may aggravate some socio-spatial inequalities in health in Europe. Conclusions The second generation of exposome research doubles down on the initial ambition of an integrative study of the environmental effects of health to fuel better public health interventions. This intensification is, however, accompanied by significant epistemological challenges and doesn't help to overcome severe restrictions in the geographical and political scope of this knowledge. We thus advocate for increased reflexivity over the limitations of this conceptually and methodologically integrative approach to public and environmental health.