The calcineurin inhibitors (CNIs) have been the cornerstone of immunosuppressive therapy in recent years, though their association with dose-related nephrotoxicity is a major factor in the development of chronic allograft nephropathy in kidney transplant recipients. The novel proliferation signal inhibitor everolimus (Certican) has a mode of action distinct and complementary to the CNIs, which is thought to underlie the demonstrated synergy between everolimus and cyclosporine (CsA) in preclinical models. This finding suggests that everolimus may allow for CNI dose reduction, enabling nephrotoxicity to be minimized without compromising efficacy. Two prospective, multicenter, randomized studies have investigated the efficacy and safety of everolimus (1.5 or 3.0 mg/day) combined with reduced-exposure CsA (Neoral) in de novo renal transplant patients. In these studies, the everolimus trough level was maintained at > or =3 ng/ml with therapeutic drug monitoring and the CsA dose optimized with C(2) monitoring. The incidence of efficacy failure with this regimen was shown to be comparable with that provided by regimens employing full-dose CNIs, but with good renal function. Furthermore, everolimus (trough levels 3-8 ng/ml) plus reduced-exposure CsA was associated with a marked reduction in acute rejection compared with regimens using fixed-dose everolimus or mycophenolate mofetil plus full-dose CsA. At 12 months follow-up, CsA trough level was 57% lower in these trials than in previous trials in which patients received full-dose CsA. This suggests that concentration-controlled everolimus can be successfully combined with optimized administration of CsA and that this regimen may maximize immunosuppression, whilst preserving renal function.