To realistically assess the human health risks associated with exposures to environmental pollutants, the authors must understand a number of important physical, chemical, and biological processes and mechanisms. This suggests that real progress in enhancing the accuracy and precision of health risk assessments depend on the products of a research program focused on the underlying mechanisms of exposure, dose, and effects. Although much of the U.S. Environmental Protection Agency's (EPA's) base research program has been targeted historically on these issues, substantial benefits can still be gained from instituting a new, more focused research program aimed specifically at reducing the critical uncertainties associated with health risk assessments. The goal of the program, known formally as the Research to Improve Health Risk Assessments (RIHRA) Program, is to generate research results that will significantly improve the EPA's ability to assess human health risks. The RIHRA program is structured so that the research products are germane to a cross-section of the Agency's regulatory programs and risk assessment needs. The authors are confident that the mission-oriented research described in the document will provide the EPA with credible scientific findings that are relevant for risk assessment decisions.