Polycystic kidney disease (PKD) is a life‐threatening genetic disorder characterized by the presence of fluid‐filled cysts primarily in the kidneys. PKD can be inherited as autosomal recessive (ARPKD) or autosomal dominant (ADPKD) traits. Mutations in either the PKD1 or PKD2 genes, which encode polycystin 1 and polycystin 2, are the underlying cause of ADPKD. Progressive cyst formation and renal enlargement lead to renal insufficiency in these patients, which need to be managed by lifelong dialysis or renal transplantation. While characteristic features of PKD are abnormalities in epithelial cell proliferation, fluid secretion, extracellular matrix and differentiation, the molecular mechanisms underlying these events are not understood. Here we review the progress that has been made in defining the function of the polycystins, and how disruption of these functions may be involved in cystogenesis. WIREs Dev Biol 2014, 3:465–487. doi: 10.1002/wdev.152This article is categorized under: Signaling Pathways > Global Signaling Mechanisms Birth Defects > Organ Anomalies