Approximately 1.1 million laboratory rodents (mice and rats) are used for biomedical research in the United States (Carbone, 2021). Contributing to the large animal numbers is the genetically modified mouse. Hundreds, if not thousands, of different strains of mice have been developed to better understand human disease. The principles of replacement, reduction, and refinement, known as the 3Rs, are crucial in ensuring the ethical treatment of research animals. In accordance with US federal law, it is the responsibility of the Institutional Animal Care and Use Committee to oversee the ethical use of animals in biomedical research. Many biomedical research institutions continue to face challenges in upholding the principles of the ‘3Rs’, particularly in the aspect of reduction. Here I assess the promotion of the 3Rs, specifically reduction, and welfare in the regulations and standards set by the US government for research involving animals. Additionally, NIH-funded peer institutional policies and staff training related to laboratory mouse breeding and colony management were also examined. Upon review and in line with the existing literature, it is crucial to consistently emphasize the significance of the 3Rs and animal welfare to research staff. These principles should be integral to training programs, actively implemented by all individuals engaged in animal research oversight, and regularly referenced by regulatory agencies.