Recent advances in clinical islet transplantation have clearly demonstrated that this procedure can provide excellent glycemic control and often insulin independence in a population of patients with type 1 diabetes. A key limitation in the widespread application of clinical islet transplantation is the requirement of 10,000 islet equivalents/kg in most recipients, generally derived from two or more cadaveric donors. It has been determined that a majority of the transplanted islets fail to engraft and become fully functional. In this review article, the factors that contribute to this early loss of islets following transplantation are discussed in depth.