Cyclosporin A (CSA) has transformed clinical transplantation, both in term of success and of quality-of-life of the patient. Studies aimed to unfold the site of CSA action have shown that this molecule binds to cytosolic proteins of the cyclophilin family. CSA:cyclophilin complexes have a high affinity for calcineurin, a key enzyme in T-cell activation. By blocking the calcineurin activity, CSA prevents the induction of genes encoding for cytokines and their receptors. Thus, humoral and cellular immune responses are abolished, this resulting in the successful graft acceptance. Disappointingly, CSA and the other molecules as FK506, sharing the capacity to inhibit calcineurin, should be administered for all patient life, as tolerance to alloantigens is not achieved by these molecules. The long term utilization of this class of immunosuppressors increases the incidence of different tumors. The finding that CSA does not interfere with various biochemical pathways has prompted different groups to analyze a possible effect of CSA on molecules that might be involved in different functions of the immune response and / or in tumorogenesis. A new picture of CSA mode of action is emerging in which the immunosuppressor prevents the transcription of a group of genes, concomitantly inducing the transcription of another set. Here, we review the data and discuss the consequences of these new findings in term of T-cell activation mechanisms.