Cyclosporine (CsA) is currently the basis of most immunosuppressive protocols after solid organ transplantation. The introduction of Neoral, a new microemulsion formulation of CsA, and more recently a range of adjunctive immunosuppressants have further enhanced short-term efficacy and tolerability of CsA-based immunosuppression. In addition, Neoral C2 monitoring has been shown to have advantages not only in the early posttransplant period, but also for maintenance transplant patients. The major long-term disadvantage associated with CsA is the development of nephrotoxicity and chronic allograft nephropathy (CAN), which is the second major cause of graft failure. Thus, strategies to reduce the risk of CAN include CsA-sparing protocols, use of C2 level monitoring, introduction of non-nephrotoxic adjunctive immunosuppressants, and optimal management of additional risk factors. Other important side effects related to CsA-based immunosuppression include hypertension, diabetes, and hyperlipidemia. Optimal management of these conditions may lead to significant reduction of cardiovascular-related morbidity and mortality following solid organ transplantation.