Transplantation of islet of Langerhans represents a viable therapeutic option for insulin-dependent diabetes mellitus. Dramatic progress has been recently reported with the introduction of a glucocorticoid-free immunosuppressive regimen that improved success rate, namely, insulin independence for 1 year or more, from 8% to 100%. The fate of islet grafts is determined by many concurrent phenomena, some of which are common to organ grafts (i.e. rejection), while others are unique to nonvascularized cell transplants, including transplant cell mass and viability, as well as nonspecific inflammation at the site of implant. Moreover, islet grafts lack clinical markers of early rejection, making it difficult to recognize imminent rejection and to implement intervention with graft-saving immunosuppressive regimens. In the present review, we will address the problems influencing islet graft success and the monitoring of islet cell graft function.