Many organs such as the salivary glands, kidney and lung form multiple epithelial clefts during the process of branching morphogenesis in embryonic development. The salivary gland provides an excellent model for clarifying the mechanism of this phenomenon. Extracellular matrix molecules regulate the dynamics of this complex process of organ formation. Nevertheless, the mechanism of cleft formation is poorly understood. Here we describe that a combination of laser microdissection with T7-SAGE has been established as a method for gene discovery of candidate molecules that may be essential for early organ morphogenesis. We show a current approach that promises to improve our understanding of the early morphological changes. We are attempting to find novel regulators of branching morphogenesis. Fibronectin, laminin gamma 2, and TIMP-3 are differentially expressed in developing clefts or buds of submandibular glands. Fibronectin-mediated crosstalks between integrin cell-to-matrix and cadherin cell-to-cell adhesion systems promote the formation of clefts. We have started studies to identify and characterize new molecules that may be important for cleft formation and fibronectin expression. We will introduce recent findings and future plans to identify new functional regulators. Progress in understanding the mechanisms of branching morphogenesis will provide novel approaches to future tissue engineering or regeneration of damaged organs.