In the past decades, allograft survival improved because of the development of new and more specific immunosuppressive agents. The introduction of calcineurin inhibitors was a landmark and acute rejection in organ transplantation decreased remarkably. Calcineurin inhibitor such as ciclosporin A inhibits T-cell activation by interfering with the cytosolic protein cyclophilin (immunophilin). This complex of ciclosporin and cyclophilin inhibits calcineurin, which is responsible for activating the transcription of interleukin-2. More recent research revealed a second pathway for T-cell activation, which is mediated by a specific protein kinase C., e.g., protein kinase C theta. AEB071 represents a selective protein kinase C inhibitor with promising potential for immunosuppression in organ transplantation. In pre-clinical studies, AEB071 prolonged allograft survival in kidney and heart transplant models. In human clinical studies, AEB071 reduced severity of psoriasis symptoms and has shown to be safe up to 750 mg single dose treatment. Important adverse events were gastrointestinal disorders and headaches. AEB071 inhibits early T-cell activation via a calcineurin inhibitor independent pathway and is currently investigated as a therapeutic agent to prevent allograft rejection after renal transplantation.