Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of inherited childhood nephropathy ( approximately 1:20,000 live births) characterized by fusiform dilatation of collecting ducts and congenital hepatic fibrosis. Up to 30% die as neonates due to respiratory insufficiency and the majority of surviving infants develop hypertension. Progression to end stage renal disease occurs in 20-45% of cases within 15 years but a proportion maintain renal function into adulthood where complications of liver disease predominate. The ARPKD disease gene, PKHD1, has recently been identified through analysis of an orthologous animal model, the PCK rat. PKHD1 is a large gene ( approximately 470 kb) with 67 exons from which multiple transcripts may be generated by alternative splicing. It is highly expressed in kidney, with lower levels in liver and pancreas. The ARPKD protein, fibrocystin (4074 aa and 447 kDa), is predicted to be an integral membrane, receptor-like protein containing multiple copies of an Ig-like domain (TIG). Fibrocystin is localized to the branching ureteric bud, collecting and biliary ducts, consistent with the disease phenotype, and often absent from ARPKD tissue. In common with other PKD-related proteins, fibrocystin is localized to the primary cilia of renal epithelial cells, reinforcing the link between ciliary dysfunction and cyst development. Screens of PKHD1 have revealed 119 different mutations of various types spread throughout the gene. Several ancestral changes have been described, some localized to specific geographic populations. The majority of patients are compound heterozygotes and preliminary genotype/phenotype studies associate two truncating mutations with severe disease. The complexities of PKHD1, marked allelic heterogeneity and high level of missense changes complicate gene-based diagnostics.