A substantial proportion of the transplanted islet mass fails to engraft due to death by apoptosis, and a number of strategies have been explored to inhibit beta-cell loss. Inhibition of extrinsic signals of apoptosis (i.e., cFLIP or A20) have been explored in experimental islet transplantation but have only shown limited impact. Similarly, strategies targeted at intrinsic signal inhibition (i.e., BCL-2) have not yet provided substantial improvement in islet engraftment. Recently, investigation of downstream apoptosis inhibitors that block the final common pathway (i.e., X-linked inhibitor of apoptosis protein [XIAP]) have demonstrated promise in both human and rodent models of engraftment. In addition, XIAP has enhanced long-term murine islet allograft survival. The complexities of both intrinsic and extrinsic apoptotic pathway inhibition are discussed in depth.