Cyclosporine (CsA) therapy has evolved considerably since its introduction as the primary immunosuppressant drug in the early 1980s and its use in renal transplantation continues to expand globally. In the last 20 years, there have been significant advances in formulation design, therapeutic drug monitoring guidelines, and the emerging role of CsA-based combination therapies that have resulted in a substantial improvement in clinical outcomes in renal transplant recipients. The aim of this work is to review developments in the application of CsA in kidney transplantation at our Center in Padua and to evaluate the clinical outcome of our patients in the last 15 years in relation to the new trends in CsA management strategies.