Perfect surgical techniques and adequate immunosuppression are key to ensuring optimal graft and patient survival. The availability of different drugs has led to several, often industry-driven, heterogeneous clinical trials to discover an ideal immunosuppressive regimen. However, the considerable and conceptually diverse study designs have failed to afford a clear definition of the optimal immunosuppression regimen. The triple-drug immunosuppressive regimen, based on the calcineurin inhibitor tacrolimus, antimetabolites mofetil mycophenolate or azathioprine, and short-term steroids—beyond possible induction—remains the currently accepted standard immunosuppression in liver transplantation. However, this regimen needs to be challenged in light of the changing definitions of rejection, customization of the immunosuppressive load, and long-term side effects due to chronic immunosuppression. Future trials should preferably include more than a single endpoint rather than acute T-cell-mediated acute rejection (a-TCMR) or kidney failure. Conversely, a comprehensive endpoint that covers patient and graft survival rates and the incidence of both acute and chronic rejection is warranted. These immune phenomena should be examined in light of serial long-term biological and histological follow-up. The diagnosis and treatment of clinically relevant a-TCMR should be based on integrated biological, immunological, and histopathological findings. Both elements are critical to progress toward more prudent immunosuppression handling and favor clinical operational tolerance.