In this review we wish to update the progress which has been made in the art of xenotransplantation (the application of living animal-derived cells, tissues and organs for transplantation in humans), with a special emphasis on the barriers of its use as a clinical therapy. A brief overview of the history of xenotransplantation reveals the greatest barrier to clinical success: hyperacute rejection, a complement-mediated response to the source animal tissue that results in the destruction of xenografts within minutes. In the past decade, great progress has been made in countering this form of rejection, but further success is thwarted by the gradual awareness of subsequent processes of rejection and physiological incompatibilities. Nonetheless, reluctance to move forward to clinical application is predominantly related to the fear that xenotransplantation will unleash a new infectious disease in the prospective recipient and his or her surroundings. Animal breeders and caretakers play an important role in ensuring that the use of the source animals for this emerging therapy does not generate a xenozoonotic pandemic.