Transplantation specificity and protective immunity occur in both adaptive and innate branches of the vertebrate immune system. However, the mechanisms which underlie the specificity, development, and self-tolerance of innate recognition strategies are not well understood. Botryllus schlosseri is born a chordate tadpole larva and later metamorphoses to an invertebrate adult, and represents the evolutionary transition between invertebrates and vertebrates. B. schlosseri also undergoes a naturally occurring transplantation reaction when two individuals come into contact which will result in either fusion of extracorporeal blood vessels to form natural chimeras, or an active, blood-based, cell-based immunity which blocks vascular fusion. This reaction is controlled by a single, highly polymorphic locus called the fuhc. In the last round of funding we isolated the fuhc locus by positional cloning and identified a highly polymorphic single gene which predicts histocompatibility outcomes in wild-type individuals. In addition, we also identified a putative group of receptors linked to the fuhc, the fester family, which we have shown are functionally involved in allorecognition events. The fuhc is one of the most polymorphic genes ever described, with normal populations having tens to hundreds of alleles. However, the ascidians do not have somatic diversification processes, such as recombination or somatic hypermutation found in vertebrate immunity. Thus an innate effector system demonstrates exquisite discriminatory ability, and our long-range goal is to dissect the cellular molecular mechanisms responsible.