Multicenter clinical trials conducted in the United States and Europe to compare the efficacy and safety of cyclosporine with tacrolimus (FK506) have demonstrated comparable long-term patient survival and graft survival in liver and renal transplant recipients. Importantly, treatment with tacrolimus was associated with reductions in the incidence and severity of acute rejection episodes. However, tacrolimus-based therapy was also associated with increased toxicities in comparison to conventional cyclosporine-based therapy. It is becoming increasingly accepted that earlier trials may have employed high or supratherapeutic doses of tacrolimus and may have been unbalanced with respect to study design. In addition, these pivotal comparative trials were performed with the original formulation of cyclosporine, and not the cyclosporine microemulsion preparation. This critical review of the literature focuses on the United States and European tacrolimus multicenter clinical trials and examines the efficacy and safety of the two primary immunosuppressants, cyclosporine and tacrolimus, obtained in these and other studies. The preliminary findings of ongoing studies comparing the efficacy and safety of the improved formulation, cyclosporine microemulsion, with tacrolimus are also discussed. The overall efficacy of the two agents appears to be similar. The safety profile shows differing toxicities of the two medications. The availability of these two immunosuppressants allows the clinician improved options when choosing an immunosuppressive regimen in solid organ transplantation.