The Office of Prevention, Pesticides, and Toxic Substances (OPPTS) of the US Environmental Protection Agency (EPA) grapples with testing issues on a daily basis. In this discussion, the current practices within OPPTS that relate to refining, reducing, and replacing (the 3Rs of) animal use are explained, based on the authors' experience. Pertinent background about EPA and OPPTS is first described, and then some broad opportunities for implementing the 3Rs are reviewed. Finally, information about how the programs in OPPTS are making progress with regard to the 3Rs is presented.