Recent clinical breakthroughs indicate that pancreatic islet allografts can reliably reverse diabetes in insulin-dependent patients. However, there are only a limited number of cadaveric organ donors available for islet isolation. There has been an ongoing effort to develop alternative donor sources. Animal tissues form an attractive donor alternative because they can be generated in large numbers and are amendable to genetic engineering. However, there is much less understanding of cellular and humoral immunity to islet xenografts relative to studies of allograft immunity. Furthermore, there is very little information regarding the capacity for generating tolerance to islet xenografts. This review centers on animal models of islet rejection and tolerance. Much discussion focuses on cellular immunity to xenografts in mouse models because most studies have been performed in such small animal systems. Evidence suggests that there is a formidable antigen-specific cellular response to islet xenografts that involves a major contribution of CD4 T cell-mediated donor antigen recognition.