Perforin is a pore-forming protein that regulates the entry of pro-apoptotic granzymes into cells targeted by cytotoxic T lymphocytes and natural killer cells. As the product of a single copy gene that enables granzyme access to their intra-cellular substrate, perforin is potentially an excellent target for the development of focused immunosuppressive drugs. Our group has developed a number of lead chemical series that potently inhibit perforin-mediated target cell death, as exemplified in a variety of in vitro assays and pre-clinical mouse models. Data will be presented showing that small molecule peforin inhibitors protect mouse bone marrow stem cells against allogeneic destruction and the survival of hepatocytes targeted by auto-reactive cytotoxic T lymphocytes in mice infected with hepatotropic adenovirus. In the latter model, short term (2 day) perforin inhibition delivered I/P was highly effective at protecting mice against fulminant liver failure resulting from adenovirus-induced hepatitis.