Since the earliest days of transplantation, immunobiologists have sought means to prevent recognition and rejection of foreign tissue. The goal of these strategies is the retention of recipient immune function while selectively avoiding graft injury. Although considerable theoretical and technical problems remain, an analogous problem and solution already exists in nature. Here, we discuss the mechanisms by which organisms preclude or control autotoxicity, and for each, consider the corollaries between prevention of autotoxicity and graft rejection. Further study of these controls, including structural and conditional tolerance and accommodation, will offer insight into new therapies for allo- and xenotransplantation.