The clinical management of tacrolimus, a macrolide used as immunosuppressant after transplantation, is complicated by its narrow therapeutic index in combination with inter- and intraindividually variable pharmacokinetics. As a substrate of cytochrome P450 (CYP) 3A enzymes and P-glycoprotein, tacrolimus interacts with several other drugs used in transplantation medicine, which also are known CYP3A and/or P-glycoprotein inhibitors and/or inducers. In clinical studies, CYP3A/P-glycoprotein inhibitors and inducers primarily affect oral bioavailability of tacrolimus rather than its clearance, indicating a key role of intestinal P-glycoprotein and CYP3A. There is an almost complete overlap between the reported clinical drug interactions of tacrolimus and those of cyclosporin. However, in comparison with cyclosporin, only few controlled drug interaction studies have been carried out, but tacrolimus drug interactions have been extensively studied in vitro. These results are inconsistent and are of poor predictive value for clinical drug interactions because of false negative results. P-glycoprotein regulates distribution of tacrolimus through the blood-brain barrier into the brain as well as distribution into lymphocytes. Interaction of other drugs with P-glycoprotein may change tacrolimus tissue distribution and modify its toxicity and immunosuppressive activity. There is evidence that ethnic and gender differences exist for tacrolimus drug interactions. Therapeutic drug monitoring to guide dosage adjustments of tacrolimus is an efficient tool to manage drug interactions. In the near future, progress can be expected from studies evaluating potential pharmacokinetic interactions caused by herbal preparations and food components, the exact biochemical mechanism underlying tacrolimus toxicity, and the potential of inhibition of CYP3A and P-glycoprotein to improve oral bioavailability and to decrease intraindividual variability of tacrolimus pharmacokinetics.