Europe and the United States further the development of new toxicological tools in different ways. While the replacement of animal tests has been promoted strongly in Europe over the last decades (following the 3Rs principles--reduce, replace, refine), in the United States the vision for a toxicology in the 21st century (Tox-21c), which was prompted by the National Research Council document only 3 years ago, dominates the discussion. In both cases, there is significant political support. However, while in Europe the horizontal animal welfare legislation from 1986 (which urges the use of 3Rs methods wherever possible) currently under revision and cosmetics and chemical legislation are the primary drivers, in the United States it is mainly federal agencies, most prominently the U.S. Environmental Protection Agency (EPA), that made the implementation of the NRC report their toxicity testing strategy only in 2009. This preempts such likely legislative measures as the reauthorization of the Toxic Substances Control Act (TSCA) in the United States. The European implementation is characterized by substantial broad funding programs to develop 3Rs methods and can be termed a "bottom-up" approach; in contrast, the Tox-21 program represents a "top-down" approach, where programmed research is carried out and commissioned. It is postulated that the two approaches are two sides of the same coin, and instruct and complement each other. However, more importantly, if brought together they can result in a Human Toxicology Project and a real revolution in regulatory toxicology.