This review presents a survey of studies of the movement of chemotherapeutic drugs into cells, their extrusion from multidrug-resistant (MDR) cells overexpressing P-glycoprotein (Pgp), and the mode of sensitization of MDR cells to anticancer drugs by Pgp modulators. The consistent features of the kinetics from studies of the operation of Pgp in cells were combined in a computer model that enables the simulation of experimental scenarios. MDR-type drugs are hydrophobic and positively charged and as such bind readily to negatively charged phospholipid head groups of the membrane. Transmembrane movement of MDR-type drugs, such as doxorubicin, occurs by a flip-flop mechanism with a lifetime of about 1 min rather than by diffusion down a gradient present in the lipid core. A long residence time of a drug in the membrane leaflet increases the probability that P-glycoprotein will remove it from the cell. In a manner similar to ion-transporting ATPases, such as Na+,K(+)-ATPase, Pgp transports close to one drug molecule per ATP molecule hydrolyzed. Computer simulation of cellular pharmacokinetics, based on partial reactions measured in vitro, show that the efficiency of Pgp, in conferring MDR on cells, depends on the pumping capacity of Pgp and its affinity toward the specific drug, the transmembrane movement rate of the drug, the affinity of the drug toward its pharmacological cellular target, and the affinity of the drug toward intracellular trapping sites. Pgp activities present in MDR cells allow for the efficient removal of drugs, whether directly from the cytoplasm or from the inner leaflet of the plasma membrane. A prerequisite for a successful modulator, capable of overcoming cellular Pgp, is the rapid passive transbilayer movement, allowing it to reenter the cell immediately and thus successfully occupy the Pgp active site(s).