Biomedical research relies on limited animal models to address questions related to human health. The limitations of inbred or genetically modified rodent models has become especially clear recently based on a number of high profile publications showing limited animal to human translation. Historically, many key discoveries have been generated by studies on a range of animals adapted to unusual environments. For example major advances in the understanding of the microcirculation continue to come from studies of the bat wing. In this context, the goal of this symposium is to explore what might be described as the “re-emergence” of comparative physiology to address important questions in human health and disease. It will also highlight sex differences in blood pressure regulation in humans. This talk will provide a brief historical overview of the issues outlined above and also highlight areas such as hypoxia tolerance, and maintenance of bone and muscle mass during extreme inactivity where there are comparative “solutions” to problems with high relevance to human health and disease.