Biomedical investigations utilize animal models to elucidate human disease processes at the cellular and molecular level and for the development of new therapies. Traditionally, these have been limited to the mouse, due to characterized genetic lines and the ability to manipulate the genome to directly test hypotheses regarding causal mutations and their linkage to disease phenotypes. The recent availability of large animal genomic sequences permits utilization of the animals whose phenotype best approximates the human condition. Equally important is the use of somatic cell nuclear cloning (SCNT) coupled with targeted germline manipulation to create animals to resolve the molecular mechanisms of the disease state. Thus, investigators can now select animals that recapitulate the human phenotype for study. Also, the availability of genomic sequence supports the evaluation of spontaneous diseases in large animals with respect to their relevance to human diseases. The ability to fully utilize large animal models supports broader aspects of translational research with respect to interventional strategies. Particularly those diseases where the disease phenotype is affected by diet or requires surgical or other therapeutic approaches utilized in human clinical medicine. Examples of the utilization of large animal models in cancer, transplantation and cardiovascular diseases will be shared.