Most cancer deaths result from the cancer either being intrinsically resistant to chemotherapeutic drugs, or becoming resistant after being initially sensitive (Leyland-Jones, Dalton, Fisher & Sikic, 1993). Often, in cells grown in cell culture, drug resistance correlates with the presence of one or more of the so-called P-glycoproteins or multidrug resistance (MDR) proteins, products of the mdr family of genes (Endicott & Ling, 1989). The mdr genes (with two forms in humans (MDR1 and MDR2), and three (mdr1, mdr2 and mdr3) in mice and hamsters) have been cloned, sequenced (Gros, Croop & Housman, 1986) and shown to be members of the 'ABC' (ATP binding cassette) or 'traffic ATPase' superfamily (Doige & Ames, 1993). All members of this superfamily (which includes the CFTR chloride ion channel, the product of the STE6 gene in yeast that transports the [alpha]-mating factor polypeptide, bacterial protein translocator HlyB that exports haemolysin, and many bacterial permeases) have a membrane transport function and share homologous sequences that often bind ATP (Kane, Pastan, Gottesman, 1990; Gros & Buschman, 1993) and can hydrolyse it. Human MDR1 and mouse mdr1 and mdr3 (Tang-Wai, Kajiji, Dicapua, de Graaf, Roninson & Gros, 1995) confer multidrug resistance, while human MDR2 and mouse mdr2 transport phosphatidylcholine and function as lipid translocases (Smit et al. 1993). The genes have tandem repeated structures, each coding for polypeptide sequences which putatively straddle the membrane six times, and each containing an ATP-binding region. The MDR genes code for glycoproteins of molecular weight 150000-180000. In drug-resistant cells, the genes are generally present as multiple repeats on episomes. Some clinical studies show that expression of the MDR1 gene is enhanced in drug-resistant tumours in patients and that this expression is a good predictor of resistance (Chan et al. 1991).Expression of the mdr genes is associated with a greatly increased resistance to the killing action of many cytotoxic drugs (Biedler & Riehm, 1970; Johnson, Chitnis, Embrey & Gregory, 1978). It brings about a marked (up to fiftyfold) reduction in the cellular steady-state level of its numerous 'substrates' (Dano, 1973; Inaba, Kobayashi, Sakurai & Johnson, 1979; Fojo, Akiyama, Gottesman & Pastan, 1985) which are fairly hydrophobic compounds but possess also some hydrophilicity. Many of these substrates are weak bases. Some bear permanent positive charges (Lampidis et al. 1989), but zwitterions seem not to be substrates. The MDR protein transports such drugs actively out of the cells in which the mdr gene is expressed (Lankelma, Spoelstra, Dekker & Broxterman, 1990; Dordal, Winter & Atkinson, 1992), that is, it is a drug pump. The protein can be present in as many as 8 × 105 (Sehested, Simpson, Skovsgaard & Jesnsen, 1989; Demant, Sehested & Jensen, 1990) or even 3 × 106 (Shapiro & Ling, 1994) copies per cell. Resistance is reversed by numerous compounds, termed 'reversers', 'modulators', or 'chemo-sensitizers' (e.g. verapamil; Tsuruo, Iida, Yamashiro, Tsukagoshi & Sakurai, 1982) and also by other MDR substrates (Horio, Lovelace, Pastan & Gottesman, 1991). P-glycoprotein has been isolated from cell membranes and demonstrated to be an ATPase, with a turnover number of some 25 s-1 at 37¡C (Ambudkar, Lelong, Zhang, Cardarelli, Gottesman & Pastan, 1992; Urbatsch, Al-Shawi & Senior, 1994; Sharom, Yu, Chu & Doige, 1995). P-glycoprotein is often present in tissues and at tissue surfaces that transport water and nutrients (kidney, gut, the blood-brain barrier; Thiebaut, Tsuruo, Hamada, Gottesman, Pastan & Willingham, 1987; Lum & Gosland, 1995), but is also present in the pancreas.What might be the physiological role of the P-glycoproteins? It was early suggested that they may be concerned in the protection of the organism from toxic, perhaps mutagenic, xenobiotic substances (Gottesman & Pastan, 1988). Their appearance in cytotoxin-resistant tumours would be an example of the ectopic expression of genes that is so often encountered in tumours. P-glycoprotein thus acts as a double-edged sword, protecting its wielder in most situations, at the expense of aiding in his or her destruction when tumours have already developed (Gottesman & Pastan, 1988). Studies using animals in which one or other mdr gene has been knocked out have thrown light on the matter. Thus, Schinkel et al. (1994), in an elegant study using mice with a knock-out mutation in the mdr1A gene, have shown that the P-glycoprotein is a major component of the blood-brain barrier, ensuring that lipid-soluble toxins (ivermectin, for example) are pumped out of the brain tissues across that barrier, protecting the organism against brain damage. P-glycoprotein acts also to keep intracellular drug concentrations low in a number of other body tissues. Blocking P-glycoprotein using knock-out mice (Schinkel et al. 1994) or by the addition of reversers of P-glycoprotein (Lyubimov, Lan, Pashinsky, Ayesh & Stein, 1995) leads to a significant rise in the tissue content of vinblastine. The tissues in which P-glycoprotein brings about a reduced concentration of cytotoxin are, in many cases, just those that are intrinsically resistant to chemotherapy by cytotoxins (Lum & Gosland, 1995).There is no fully accepted model for the mechanism of action of this important molecule. There is much evidence that P-glycoprotein behaves quite differently from conventional membrane pumps. The 'vacuum cleaner' model (Raviv, Pollard, Bruggemann, Pastan & Gottesman, 1990), in which P-glycoprotein is a machine that cleans its substrates out of the plasma membrane, and delivers them to the exterior aqueous phase, provides an intriguing general framework for discussion of the pump's action and is the basic standpoint of this paper.