Over the last two decades, gene transfer experiments for the treatment of inherited or acquired diseases have mainly been performed in mice. While mice provide proof of principle and allow testing of a variety of therapeutic modalities, mouse models have some limitations, as only short-term experiments can be performed, their homogenous genetic background is unlike humans, and the knockout models do not always faithfully represent the human disease. Naturally occurring large animal models of human genetic diseases have become increasingly important despite the costs and the extensive clinical attention they require because of their similarities to human patients. Large animals are reasonably outbred, long lived allowing for longitudinal studies, are more similar in size to a neonate or small child providing an opportunity to address issues related to scaling up therapy, and many physiological parameters including the immune system are more similar to those in humans versus those in mice.