The mouse has not always been the model of choice to study physiology. Over many years a whole array of animal models have been used including rat, dog, rabbit, guinea pig, chick, zebrafish and fruit fly, providing valuable information about cardiovascular physiology, the immune system, embryonic development, circadian rhythm and the nervous system, to name a few. It was the advent of transgenesis and the ability to genetically manipulate the mouse genome that led to a revolution in the use of the mouse as the go-to model in which to study mammalian gene function in vivo. However, does the fact that we can readily manipulate the genome of the mouse make it an appropriate model in which to study human physiology and pathophysiology? It is clear that humans and mice are very different but they do have important essential similarities. They share considerable genetic homology, with 99% of their genes being the same, and with key physiological and cellular similarities for example in their cardiovascular, nervous, musculoskeletal, endocrine and immune systems. That said, it is important at this point to insert the caveat that there are also a number of physiological differences in these systems. Whilst recognising the inherent limitations of any model system I will argue that the mouse is our most valuable model to further our understanding of physiology and pathophysiology.