As experience with tacrolimus (FK506, Prograf) accumulates and reduced rejection rates are increasingly demonstrated, some transplant centers are adopting tacrolimus-based primary immunosuppressive regimens for their patients undergoing pancreas/kidney transplantation. The guidelines provided in this article based on the experience of four major US transplant centers, cover issues related to dosing, blood levels, concomitant use of mycophenolate mofetil (MMF), antifungal and antiviral prophylaxis, and drug interactions. For post-transplant immunosuppression some centers initiate oral tacrolimus administration on postoperative day 1, 2, or 3, while others wait until day 6 or 7, when renal or gastrointestinal function has resumed. Most centers endeavor to achieve higher target trough levels (approximately 10-20 ng/mL, but not higher) in the first 3 months post-transplant, reducing levels thereafter. Several centers are now using MMF instead of azathioprine as an adjunct to tacrolimus. Conversion from cyclosporine to tacrolimus during maintenance therapy is often considered in the event of rejection or when adverse events do not respond to dosage reduction.