Exceptionally low acute rejection rates and excellent graft survival can be achieved with cyclosporine and tacrolimus (CNI)-based immunosuppressive protocols that incorporate antiproliferative immunosuppressants and corticosteroids. However, despite short-term success, long-term attrition of graft function and side effects of immunosuppressive agents continue to be significant problems, leaving clinicians looking for possible interventions. CNI nephrotoxicity is but one of numerous factors that may contribute to long-term damage in transplant kidneys. Metabolic, cosmetic, and neuropsychiatric complications of steroids affect quality of life after transplantation. Newer immunosuppressive agents such as mycophenolate mofetil and sirolimus (Rapa) have raised the possibility of withdrawing or avoiding CNIs or steroids altogether. In this report we review studies that address either CNI or steroid minimization strategies and discuss their risks versus benefits. Given the accumulated experience to date, in our opinion the use of CNIs and steroids as part of immunosuppressive regimens remains the proven standard of care for renal transplant patients. The long-term safety and efficacy of CNI and steroid minimization strategies needs to be further validated in controlled clinical trials with adequate long-term follow-up.