Basic concepts in transplantation immunology have been recently revisited. Accordingly, the immune response towards an allograft is not anymore considered as necessarily harmful, but could participate, under certain conditions, to graft acceptation through active mechanisms. This novel paradigm was progressively evaluated in clinical liver transplantation, with the aim to minimize the immunosuppressive regimens and, as a first step, to completely withdraw steroids from the immunoprophylactic regimen. The development of laboratory tests to reproducibly assess the immune reactivity of a recipient towards his/her transplanted organ should allow the identification of operationally tolerant patients, and the elective withdrawal of maintenance immunosuppression in this subgroup.