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The U.S. Department of Energy (U.S. DOE) sponsors a research program aimed at gaining a better understanding of how low-dose radiation affects cellular functioning and progression toward disease. There have been calls to incorporate into regulatory decision-making the scientific information that this program has produced. After a discussion of the evolution of radiation protection law and the weight-of-evidence approach that agencies employ, this paper offers some preliminary thoughts about how to approach this complex and important policy question. Three implementation challenges are identified and discussed. The first implementation challenge involves explaining low-dose effects in a systems biology model. The second challenge arises when issues of population susceptibility are juxtaposed against molecular and mechanistic studies, such as those that make up much of the U.S. DOE low-dose program. The third challenge concerns integrating the results of radiation epidemiology, especially epidemiologic studies among cohorts that are exposed to low dose and low-dose rate radiation, with the results of U.S. DOE low-dose studies.