© 2020 Elsevier Inc. All rights reserved. Despite progress in the treatment of patients with type 1 diabetes using conventional insulin therapy, clinical advances appear to have reached a plateau in improving the quality of life and reducing morbidity and mortality, particularly in those with severe hypoglycemia unawareness. Innovation is required to advance this field and improve quality of life. The ubiquitous shortage of pancreas donors and a decrease in the number of whole pancreas transplants in the past decade has called for exploration of other approaches to β-cell replacement therapy, including islet xenotransplantation. This chapter serves as a comprehensive review and resource for the evolution of islet xenotransplantation. We provide a brief history, and explore the immunological and physiological barriers to free islet xenotransplantation, and goals of treatment. In reviewing the pig-to-nonhuman primate model for translation into clinical practice, we explore the safety, efficacy, and feasibility of cross-species transplantation. Over 20 years of clinical experience is reviewed, while summarizing the most recent expert opinions on future research and the guidelines for clinical trials.