The establishment and maintenance of epithelial polarity is essential for the integrity and function of epithelial organs and is particularly critical in the kidney, where vectorial reabsorption and secretion are effected in different segments of the nephron by the differential polarized insertion of channels, transporters, and related proteins into apical membranes lining the tubule lumen or basolateral membranes adjacent to the interstitium and blood space. Faulty intracellular delivery and polarization of membrane proteins can lead to serious diseases such as cystic fibrosis, I cell disease, and renal cystic diseases. The best understood disease of epithelial polarity is autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in a >462-kDa, developmentally regulated membrane protein, "polycystin." ADPKD cysts are characteristically lined by a single layer of structurally polarized epithelial cells with normal functional intercellular tight junctions but with aberrant polarization of some important membrane proteins. Abnormal apical membrane polarity of biochemically active, ouabain-sensitive Na-K-adenosinetriphosphatase (Na-K-ATPase) in ADPKD cyst epithelia leads to abnormal sodium ion secretion and provides a mechanism for aberrant fluid secretion. In addition, apically mislocated, functional epidermal growth factor (EGF) receptors on cyst epithelia, together with EGF synthesis and secretion into cyst lumens, provide a mechanism for autocrine regulation of increased epithelial cell proliferation in ADPKD. Underlying mechanisms for these abnormalities in polarized distribution of membrane proteins include the aberrant expression of fetal gene products, such as the beta2-subunit of Na-K-ATPase, in ADPKD kidneys. Overexpression of polycystin protein in ADPKD cyst epithelia, low levels restricted to medullary collecting tubules in normal adult kidneys, and high levels in ureteric bud-derived structures in human fetal kidneys further suggest a failure of downregulation of fetal genes as a mechanism for the polarity abnormalities that characterize ADPKD.