Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in at least three different genes: PKD1, PKD2, and PKD3. ADPKD1 is an inherited disorder that has led to the discovery of a novel protein, polycystin. Polycystin, a 460 kd protein with a host of domains implicating a potential role in cell-cell and cell-matrix regulation, is encoded by a 52 kb gene with a 14 kb mRNA. The PKD2 protein is also large (110 kd) and is thought to interact with polycystin. ADPKD1 is caused by mutated DNA that encodes an abnormal form of polycystin. Polycystin appears to have a normal role in the differentiation of epithelial cells, and when defective, these cells fail to maturate fully. These incompletely differentiated cells proliferate abnormally and express altered amounts of otherwise normal electrolyte transport proteins that result in excessive secretion of solute and fluid into the cysts. The proliferation of the cells and the associated apoptosis, and the secretion of the fluid into the cysts created by the enlarging tubule segments appear to be regulated by growth factors, hormones, and cytokines that can alter the extent to which the disease is clinically expressed among individuals. The formation of the cysts is associated with complex changes in the extracellular matrix of the kidneys and other organs that may be directly or indirectly tied to mutated polycystin. The summation of these pathogenetic elements leads to renal interstitial infiltration, with monocytes, macrophages, and fibroblasts culminating in fibrosis and progressive loss of renal function. The modem understanding of cyst pathogenesis opens opportunities to develop treatments that may diminish or halt altogether the progression of this disease.