National government establishments, including regulatory agencies, are part of national science systems, which are a subset of larger national innovation systems. The forces that have influenced the basic roles of national government establishments in five countries over the past 10 yr are reviewed on the basis of a study commissioned by Industry Canada in 1999 for the Council of Science and Technology Advisors to the Canadian government. The most significant response among countries has been found to be the financial and managerial restructuring of government science and technology establishments driven by the push toward self-financing. Trends in the roles of government science and technology in six areas are also ranked, with increasing the health and safety of the nation, providing support to industry and participating in international cooperation occupying the first three positions. Potential ramifications of these trends on the implementation of the concept of replacement, reduction, and refinement (the 3Rs) in ensuring the ethical use of animals in regulatory testing are discussed. Science advice and its role in governmental decision making is reviewed on the basis of the 1999 Report of the Council of Science and Technology Advisors, Science Advice for Government Effectiveness. Six principles developed for the effective use of science advice in making regulatory decision have been adapted and are proposed with accompanying guidelines as a framework for the development of a science-based decision making process to facilitate the implementation of the 3Rs by governmental regulators. The proposed series of principles and guidelines are designed to reflect the rapidly evolving and complex context for government decision making, and to remain consistent across government departments and across nations.