Many methods for reducing the immunosuppressive requirements of allotransplantation have been proposed based on a growing understanding of physiological and allospecific immunity. As these regimens are developed for clinical application, they require validation in models that are reasonably predictive of their performance in humans. This article provides an overview of the large animal models commonly used to test immunomodulatory organ transplant protocols. The rationale for the use of large animals and the effects of common immunosuppressants in the dog, pig, and non-human primate are reviewed. Promising methods for the induction of allospecific tolerance are surveyed with references to early human trials where appropriate.