The Edmonton protocol was undoubtedly a major step forward in the history of islet transplantation. Its immunosuppression regimen was largely based on the mTOR inhibitor rapamycin (sirolimus), which remains the most frequently used immunosuppressive drug in clinical islet transplant protocols. As time reveals the somewhat disappointing long-term results achieved with the Edmonton protocol, a number of publications have appeared addressing the potential beneficial or deleterious role of rapamycin on islet cell engraftment, function survival and regeneration, as well as on its side-effects in human subjects. This paper reviews the sometimes contradictory evidence on the impact of rapamycin in islet transplantation.