Since William Bateson’s 1906 coinage of the term “genetics,” the rise of mice as a model organism for biomedical research has gone hand in hand with genomic developments. In today’s research environment, mice and rats make up the vast majority of all research subjects. While the advent of gene-editing tools such as CRISPR has made genetic manipulation of mice easier, these tools also signal a new trend toward an increased use of large animal models such as dogs, pigs, and nonhuman primates. Especially for neurological impairments, CRISPR gene editing offers the potential to generate large-animal models that better mimic human diseases. What are the ethical and regulatory implications of this trend? The professional and ethical framework for responsible conduct of animal research is widely recognized as the “three Rs”: Reduction, Refinement, and Replacement. This Article points to the tension between reduction (decreasing the overall numbers of animals used) and relative replacement (the use of mice and rats instead of species with more “complex” capacities) that is implied by such a tradeoff. The Article argues, however, that a comparative analysis of regulatory frameworks in the United States and in the European Union shows that neither offers any substantial guidance to moderate a trend toward greater use of large-animal models. Nevertheless, we raise several ethical questions associated with the trend toward using relatively fewer animals but replacing less cognitively developed animals with those with potentially greater morally relevant capacities and moral standing.