Simple SummaryNew tools, allowing scientists to make precise changes to mammal genomes, have made possible future increased use of larger mammals in biomedical research, such as primates, pigs, and dogs. This paper addresses ethical issues that are raised by using larger mammals instead of smaller ones in this research. Because scientists who use animals in research follow strict guidelines, we first examine what those guidelines suggest for using larger mammals. We then consider what philosophers, who write about the ethics of animal use, consider as the important questions in evaluating which (if any) animals are acceptable to use in research. We find that philosophical perspectives have typically been interested in the question of when or if animal use is justified, while biomedical research guidance has assumed that animal use is justified but defined specific limits to that use. To address directly the ethical questions that arise in the practice of biomedical research in selecting which animals to use, we consider an approach to ethics that is focused on character and living well (or flourishing). This paper is valuable to society in drawing attention to the ethical questions, rather than merely the scientific issues, that are important in selecting which animals to use in biomedical research.Recent developments in genome editing tools, along with limits in the translational potential of rodent models of human disease, have spurred renewed biomedical research interest in large mammals like nonhuman primates, pigs, and dogs. Such scientific developments raise ethical issues about the use of these animals in comparison with smaller mammals, such as mice and rats. To examine these ethical questions, we first consider standard (or “orthodox”) approaches, including ethics oversight within biomedical research communities, and critical theoretical reflections on animal research, including rights-based and utilitarian approaches. We argue that oversight of biomedical research offers guidance on the profession’s permitted uses of animals within a research setting and orthodox approaches to animal ethics questions when and whether animals should be used in biomedicine; however, neither approach sufficiently investigates the nuances of ethical practices within the research setting. To fill this lacuna, we consider a virtue ethical approach to the use of specific animal models in biomedicine. From this perspective, we argued that limitations on flourishing for large mammals in a research setting, as well as potential human-animal bonds, are two sources of likely ethical tensions in animal care and use in the context of larger mammals.