P-Glycoprotein (P-gp) may have a significant impact on systemic and tissue/cellular bioavailability of drugs because it functions as an "anti-absorption" mechanism that effluxes drug molecules out of the lipid bilayer and cytoplasm. The ability to reduce bioavailability at the tissue/cellular level was first discovered during the investigation of the causes of multidrug resistance (MDR) in cancer chemotherapy. Initially, it was thought that MDR is only caused by P-gp. Recently, many other transporters such as multidrug resistance-related protein (MRP) have also been identified. The ability of P-gp to impact systemic drug bioavailability was only recently recognized. Dr. Alfred Schinkel's group was first to show a significant improvement in the systemic bioavailability of several drugs in the MDR1 knockout mice. The same group also discovered that the blood-brain barrier (BBB) has a very high expression level of P-gp, and that this protein is necessary to restrict the entrance of various drug molecules into the central nervous system (CNS). Polymorphism in the normal human cells has not been reported, but it has been discovered in human cancer cells. Functional implication of P-gp polymorphism in changing the tissue bioavailability has been studied in rodents. These studies strongly support the role of P-gp in restricting tissue bioavailability of anticancer drugs. These studies also support the effectiveness of P-gp in limiting CNS toxicity of the cytotoxic drugs. The functional implication of P-gp on systemic bioavailability is much less well defined in humans, although it appears to be quite obvious in MDR1 knockout mice. Pharmacokinetic models clearly suggest that a change in the absorption rate will have a significant impact on systemic blood level of a drug. However, whether functionally significant polymorphisms of P-gp exist in humans has not been determined. If they do exist, they will surely impact on both systemic bioavailability and drug interaction potentials of many drugs. In the drug development process, several models may be used to select a lead compound that may or may not interact with P-gp, depending on whether the interaction is desirable. Several inhibitors of P-gp are currently on the clinical trial stage. Natural inhibitors of P-gp have also been discovered. There is no doubt that these new developments will have significant impact on the bioavailability of a variety of anticancer and CNS drugs in the next decades.