Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disorder. Recent molecular genetic advances have allowed identification of several genes underlying NPHP. NPHP genes encode proteins known as nephrocystins which are located in the primary cilium, basal body complex, adherens junction and focal adhesion kinase protein complexes. This shared localisation has led to a paradigm whereby all genes mutated in cystic kidney diseases express their protein products in the primary cilium and/or basal body structures, suggesting that common pathogenic mechanisms underlie this multisystem disease. Cilial proteins are highly conserved throughout evolution and their defects lead to an expanding group of conditions known as ciliopathies. Functional studies implicate nephrocystins in planar cell polarity pathways, which may be crucial for renal development and maintenance of tubular architecture. Mechanisms underlying cystogenesis and therapeutic interventions are being explored in model systems enabling new insights into this disease.