No area of medicine stimulates as much excitement or as much controversy as transplantation. The rationale for xenotransplantation is the shortage of human organs and tissues. For several reasons, however, most in the field of xenotransplantation have abandoned the use of nonhuman primates. Therefore, instead of using primates, most in the field of transplantation focus on the use of pigs or other non-primate species. If opportunities offered by xenotransplantation are great, the hurdles, at present, appear equally so. These hurdles include (i) the immune response of the host against the graft leading to rejection of the graft, (ii) the inherent physiologic limitations of the animal tissue or organ in a human system or induced disruption of the normal functions of the recipient, and (iii) the possibility of transferring infectious agents from the transplant to the recipient and, potentially, more broadly to the general population. This chapter focuses on the hurdles to transplanting porcine organs and cells into humans. The past few years have brought significant progress in defining the hurdles to xenotransplantation and progress in overcoming the immunologic and physiologic hurdles in this field.