The Precautionary Principle is founded on the use of comprehensive, coordinated research to protect human health in the face of uncertain risks. Research directed at key data gaps may significantly reduce the uncertainty underlying the complexities of assessing risk to mixtures. The National Institute of Environmental Health Sciences (NIEHS) has taken a leadership role in building the scientific infrastructure to address these uncertainties. The challenge is to incorporate the objectives as defined by the Precautionary Principle with the knowledge gained in understanding the multifactorial nature of gene-environment interactions. Through efforts such as the National Center for Toxicogenomics, the National Toxicology Program, and the Superfund Basic Research Program, NIEHS is translating research findings into public health prevention strategies using a 3-pronged approach: 1) identify/evaluate key deviations from additivity for mixtures; 2) develop/apply/link advanced technologies and bioinformatics to quantitative tools for an integrated science-based approach to chemical mixtures; 3) translate/disseminate these technologies into useable, practical means to reduce exposure and the risk of disease. Preventing adverse health effects from environmental exposures requires translation of research findings to affected communities and must include a high level of public involvement. Integrating these approaches are necessary to advance understanding of the health relevance of exposure to mixtures.