Epigenetic changes represent a potential mechanism underlying associations of early-life exposures and later life health outcomes. Population-based cohort studies starting in early life are an attractive framework to study the role of such changes. DNA methylation is the most studied epigenetic mechanism in population research. We discuss the application of DNA methylation in early-life population studies, some recent findings, key challenges and recommendations for future research. Studies into DNA methylation within the Developmental Origins of Health and Disease framework generally either explore associations between prenatal exposures and offspring DNA methylation or associations between offspring DNA methylation in early life and later health outcomes. Only a few studies to date have integrated prospective exposure, epigenetic and phenotypic data in order to explicitly test the role of DNA methylation as a potential biological mediator of environmental effects on health outcomes. Population epigenetics is an emerging field which has challenges in terms of methodology and interpretation of the data. Key challenges include tissue specificity, cell type adjustment, issues of power and comparability of findings, genetic influences, and exploring causality and functional consequences. Ongoing studies are working on addressing these issues. Large collaborative efforts of prospective cohorts are emerging, with clear benefits in terms of optimizing power and use of resources, and in advancing methodology. In the future, multidisciplinary approaches, within and beyond longitudinal birth and preconception cohorts will advance this complex, but highly promising, the field of research.