Environmental exposures have a significant influence on the chronic health conditions plaguing children and adults. Although the Developmental Origins of Health and Disease (DOHaD) paradigm historically has focused on nutrition, an expanding body of research specifically communicates the effects of chemical exposures on early-life development and the propagation of non-communicable disease across the lifespan. This paper provides an overview of 20 years of research efforts aimed at identifying critical windows of susceptibility to environmental exposures and the signaling changes and epigenetic influences associated with disease progression. DOHaD grants funded by the National Institute of Environmental Health Sciences (NIEHS) in 1991, 2001 and 2011 are identified by grant-analysis software, and each portfolio is analyzed for exposures, disease endpoints, windows of exposure, study design and impact on the field based on publication data. Results show that the 1991 and 2001 portfolios comprised metals, PCBs and air pollutants; however, by 2011, the portfolio has evolved to include or expand the variety of endocrine disruptors, pesticides/persistent organic pollutants and metals. An assortment of brain-health endpoints is most targeted across the portfolios, whereas reproduction and cancer increase steadily over the same time period, and new endpoints like obesity are introduced by 2011. With mounting evidence connecting early-life exposures to later-life disease, we conclude that it is critical to expand the original DOHaD concept to include environmental chemical exposures, and to continue a research agenda that emphasizes defining sensitive windows of exposure and the mechanisms that cause disease.