The human P glycoprotein (Pgp; MDR1) is an ATP-driven transporter for hydrophobic drugs and causes multidrug resistance in cancer. Our knowledge related to the mechanistic details of the ATP hydrolytic cycle of MDR1 has recently significantly progressed due to studies on the formation of a catalytic intermediate (occluded nucleotide state). According to the most accepted current model, both catalytic sites in MDR1 are active and ATP is hydrolysed alternatively within the two sites. ATP hydrolysis at one site triggers conformational changes within the protein resulting in drug transport, while hydrolysis of a second ATP molecule (at the other site) is required for resetting the initial ('high-affinity binding') conformation. The two active sites act in a cooperative manner and experiments support a model where the two ATP binding cassette (ABC) domains form a coupled catalytic machinery. Although no high resolution structure is available as yet, some relevant structural information can be deduced from crystal structures obtained for several bacterial ABC units, and the recently solved bacterial ABC-ABC dimer crystal structures may provide the basis for a better understanding of the intramolecular cross-talk between the two catalytic sites. As intramolecular interactions between various domains of Pgp/MDR1 are essential in regulating both the ATPase and transport activity, compounds perturbing these interactions may interfere with the function of the transporter. Such compounds, as well as various substrate analogues may be useful in modulating multidrug resistance in cancer.