PURPOSE. Neurofibromatosis type 2 (NF2) is an autosomal-dominant CNS tumor syndrome that affects 1:25,000 children and young adults. More than 50% of NF2 patients also develop posterior subcapsular cataracts (PSCs). The authors deleted Nf2 from the lens to determine its role in fiber cell differentiation. METHODS. Nf2 was conditionally deleted from murine lenses using the LeCre transgene. Standard histology and immunohistochemical and immunofluorescent methods were used to analyze lens morphology and markers of cell cycle progression, differentiation, and cell junctions in wild-type and knockout lenses from embryonic day 10.5 through postnatal day 3. RESULTS. Fiber cells lacking Nf2 did not fully exit the cell cycle and continued to express epithelial cell markers, such as FoxE3 and E-cadherin, despite expressing the fiber cell marker Prox1. Many fiber cells lost their elongated morphology. Markers of apical-basal polarity, such as ZO-1, were mislocalized along the lateral and basal membranes of fiber cells. The lens vesicle failed to separate from the surface ectoderm, and prospective lens and corneal epithelial cells formed a multilayered mass of cells at the surface of the eye. Herniation of this membrane caused the fiber mass to erupt through the cornea. CONCLUSIONS. Nf2 is required for complete fiber cell terminal differentiation, maintenance of cell polarity, and separation of lens vesicle from corneal epithelium. Defects identified in fiber cell differentiation may explain the formation of PSCs in patients with NF2. The lens provides an assay system to identify pathways critical for fiber cell differentiation and to test therapies for the tumors that occur in patients with NF2.