Several large prospective investigations are under way or are planned in different parts of the world, aiming at the investigation of gene-environment interactions for chronic diseases. Technical, practical and ethical issues are raised by such large investigations. Here we describe how such issues were approached within a case-control study nested in EPIC, a large European cohort, and the kind of validation studies that have been set up. The GenAir investigation aimed at measuring the effects of air pollution and environmental tobacco smoke on human health in EPIC with a nested design and with biological measures. Validation studies included (a) comparisons between cotinine measurements, hemoglobin adducts and questionnaire data; (b) an analysis of the determinants of DNA adduct concentration; (c) comparison among different genotyping methods; (d) an analysis of the determinants of plasma DNA amounts. We also describe how the ethical issues were dealt with in our investigation.