Research using nonhuman animals is commonly claimed to have been central to many major accomplishments of modern medicine. The cornerstone of biomedical research using nonhuman organisms is studying processes in intact organisms in order to understand the same or analogous processes in humans, including to characterize health/disease states and their associated causal mechanisms, and to test the effects of proposed therapeutics. This chapter provides an overview of key philosophical issues associated with medical research organisms, with primary focus on associated epistemic factors. It explores this evolution of the choice and use of medical research organisms and newer developments such as New Approach Methodologies (NAMs), and the corresponding transitions in how they are understood to represent humans and thus are used to establish knowledge that can be actionable for medical purposes. It raises the following key philosophical questions: How is it that medical research organisms can be viewed as models or representations for humans, and how are they used to generate valid knowledge about human health and disease?