Purpose: Signaling by members of the TGF beta superfamily of molecules is essential for embryonic development and homeostasis. Smad4, a key intracellular mediator in TGF beta signaling, forms transcriptional activator complexes with Activin-, BMP-, and TGF beta-restricted Smad proteins. However, the functional role of Smad4 in controlling different visual system compartments has not been fully investigated. Methods: Using the Pax6 promoter-driven Cre transgenic, smad4 was conditionally inactivated in the lens, cornea and ectoderm of the eyelids. Standard histological and molecular analytical approaches were employed to reveal morphological and cellular changes. Results: Inactivation of Smad4 in the lens led to microphthalmia and cataract formation in addition to the persistent adhesion of the retina to the lens and the iris to the cornea. Inactivation of Smad4 from the ectoderm of the eyelid and cornea caused disruption to eyelid fusion and proper development of the corneal epithelium and corneal stroma. Conclusions: Smad4 is required for the development and maintenance of the lens in addition to the proper development of the cornea, eyelids, and retina. (C) 2010 Elsevier Inc. All rights reserved.