Polycystic kidney disease (PKD) is a diverse group of human monogenic lethal conditions inherited as autosomal dominant (AD) or recessive (AR) traits. Recent development of genetically engineered mouse models of ADPKD, ARPKD, and nephronophthisis/medullary cystic disease (NPHP) are providing additional insights into the molecular mechanisms governing of these disease processes as well as the developmental differentiation of the normal kidney. Genotypic and phenotypic mouse models are discussed and provide evidence for the fundamental involvement of cell-matrix, cell-cell, and primary cilia-lumen interactions, as well as epithelial proliferation, apoptosis, and polarization. Structure/function relationships between the PKD1, PKD2, PKHD1, and NPHP genes and proteins support the notion of a regulatory multiprotein cystic complex with a mechanosensory function that integrates signals from the extracellular environment. The plethora of intracellular signaling cascades that can impact renal cystic development suggest an exquisitely sensitive requirement for integrated downstream transduction and provide potential targets for therapeutic intervention. Appropriate genocopy models that faithfully recapitulate the phenotypic characteristics of the disease will be invaluable tools to analyze the effects of modifier genes and small molecule inhibitor therapies.