In 1900, Abbie Lathrop began raising mice in Massachusetts for sale as pets and, afterwards, her animals were bought by several research laboratories at Harvard University. The use of rodents rapidly expanded worldwide because they need little space, are relatively inexpensive to maintain, easy to manage and have a short life cycle. After that, rats and mice have dominated biomedical research during the past century because they have a sequenced genome and are easily modified by genetic engineering. The advances obtained in biomedical research by the use of rodents are, certainly, impressive; however, there are also a number of severe limitations. The main constraints are the marked differences with humans in cell and tissue biology, metabolic and endocrine routes, and developmental patterns and physiology of organs and systems. Hence, findings in rodents are very different from those in human patients in many disease areas. A second crucial issue is the small body size of rodents, which flaws the translational application of imaging techniques and impedes the serial sampling of large amounts of blood and tissues. In this sense, different species of large animals fulfil these necessities and offer numerous profitable characteristics. Having in mind body-size, handling- easiness and cost-efficiency, the main species used in biomedical research are rabbits, sheep and swine. Sheep has been traditionally used as model in orthopaedics and regenerative medicine, respiratory diseases and reproductive endocrinology and fertility therapies. Sheep has a convenient size and temperament, which facilitate housing and handling but also sequential screening by non-invasive imaging and assessment of hormones and metabolites. Currently, the sheep is especially interesting in developmental programming because of singleton pregnancy and similar developmental trajectory to humans; screening of foetal and early postnatal development is well-established. The pig is considered an outstanding animal model for biomedical studies from long time ago and its use is currently growing even at a higher rate. Pigs share many more anatomical (including proportional organ sizes) and physiological similarities (including lifestyle: diurnal rhythms, omnivorous habits and propensity to sedentary behaviour) with humans than any other animal species. Consequently, pigs mimic human situation more accurately than other species, mainly with regards to skin, cardiovascular system, gastrointestinal tract, kidneys and spleen. Additional advantages are a convenient size and nature for housing and adequate characteristics for breeding and maintenance of strains at any time during the year (early puberty, non-seasonal breeding, short weaning-to-mating interval and high prolificacy). Moreover, the information and commercial products for housing, feeding and breeding is huge due to the importance of the species in animal production. Swine also provide breeds and strains fitting for different research objectives and, currently, the advantages of swine models have been boosted by the availability of porcine genome data, which facilitates genetic modification and creation of genetically engineered strains for specific applications in translational research. Actually, these tools will increase the usefulness of pigs as models of human health and disease and will allow the development of more specific swine models.