The proximal renal tubule is the major site of P-glycoprotein expression within the kidney; there is good evidence that P-glycoprotein expression is not restricted to the proximal tubule occurring in thick ascending limb and more distal segments. P-glycoprotein is expressed at the apical brush-border membrane where it participates in ATP-dependent extrusion of substrates to urine.The Madin-Darby canine kidney (MDCK) dog-renal epithelial cell-line is a model for renal tubular P-glycoprotein mediated secretion. The apical membrane is rendered effectively impermeable to archetype substrates such as vinblastine by a combination of low intrinsic permeability and the operation of ATP-dependent export from cytosol to the apical (lumen) solution. Since the MDCK cell-line possesses features characteristic of the distal/collecting duct, this suggests a possible role for tubular expression at distal sites in limiting back-diffusion and trapping of moderately lipophilic P-glycoprotein substrates within the renal medulla after secretion in the proximal tubule and subsequent concentration resulting from tubular fluid reabsorption.The relative role of P-glycoprotein in mediating renal clearance of archetype P-glycoprotein substrates is discussed. Due to the absence of inhibitory agents of absolute specificity a definite assessment is not yet possible. The pharmacological importance of P-glycoprotein mediated transport in renal cells is discussed in relation to renal transplantation and to treatment of renal carcinomas. The utility of transgenic knockout animal models for assessing P-glycoprotein function in renal clearance studies is highlighted.Renal polycystic disease is a major cause of renal insufficiency. Cysts arise from tubules, but are closed structures with the epithelium oriented so that the brush-border is adjacent to the closed lumen. Bodipy-verapamil has been tested as a fluorescent substrate for P-glycoprotein mediated transepithelial secretion in MDCK-C5A epithelia (selected for their ability to form cysts in vitro) reconstituted first as a monolayer on permeable substrates. Net transepithelial secretion (J n e t ) of [ 3 H]-vinblastine from basal to apical surfaces is inhibited by taxotere, verapamil and bodipy-verapamil. Bodipy-verapamil is itself subject to a saturable transepithelial net secretion by MDCK-C5A epithelia. In MDCK-C5A cysts grown in hydrated collagen gel laser scanning confocal microscopy shows that bodipy-verapamil is accumulated within the cyst lumen above medium concentrations. Renal cystic epithelial P-glycoprotein expression is exploitable to target cytotoxic P-glycoprotein substrates to renal cysts. The possible advantages of targeting cytotoxic substrates to renal cysts is discussed.