Drug bioavailability is defined as the rate and extent to which the active ingredient is absorbed from a drug reaching the site of action (receptor or legend) intact. However, due to the inaccessibility of the site of action, the drug level reaching the systemic circulation intact was adopted as a measure of bioavailability. Two agents Mycophenolate Mofetil (MMF), and Sirolimus (RAPA) were introduced as a fixed dose drugs with no need for blood level monitoring. MMF at 3g/day did not offer additional advantage to 2 g/day or 1.5 g/day dose. Moreover the side effects of MMF increased in some patients following cessation of CYA therapy and for an increase in the rate of rejection episodes following the cessation of Tacrolimus (TAC). Monitoring blood levels (BL) in these patients indicated that the concomitant administration of CYA reduces the MMF level while TAC leads to a near doubling of the MMF level. In case of RAPA it was also noticed that its efficacy and side effects were related to blood level. It was also observed that rejection episodes in certain ethnic groups such as African Americans are more frequent than those observed in Caucasians. In order to address the possibility of a universal dosing protocol we have to examine the factors affecting the bioavailability of immunosuppressive agents. We have studied the intra and inter patient variabilities in bioavailability in 693 transplant patients. We have found that the main factors affecting immunosuppressive drugs bioavailability are: 1-Absorption, which is affected by: the vehicle used in the drug, ethnic background, food intake, type of food, forms (solutions vs. capsules), GI infection, bowel movement and tablet coating and drug receptors. 2- Metabolism which is affected by: genetic factors, drug drug interaction, and disease related issues. 3-Elimination: Although elimination is not a major factor in immunosuppressive drug however, it can lead in few instances to deleterious effect especially in liver transplant patients. It is easy to determine these issues in each patient prior to transplantation which leads to a dose tailoring.