The Wnt/Wingless (Wg) pathway is one of a core set of evolutionarily conserved signaling pathways that regulates many aspects of animal development. Aberrant Wnt signaling has been linked to human disease, such as cancers of the intestine, stomach, breast, liver, and skin. Mutations in the Wnt genes or in those that encode regulators of this pathway can cause devastating birth defects, including debilitating abnormalities of the central nervous system, axial skeleton, limbs, and occasionally other organs. The focus of my laboratory is to integrate a variety of functional genomic and proteomic high-throughput screens to generate a global picture of how the Wnt signaling pathway is regulated at a molecular level. We are also interested in understanding how components of the Wnt pathway may interact with other signal transduction cascades during development and disease. We are using a newly developed technology, called RNA-interference (RNAi) to systematically knockdown gene function on a genome scale and testing the effects (phenotype) of reduced gene function on cells and in the developing embryo. The RNAi screens are used to assign new function to genes in the context of the Wnt pathway. Finally, an important aspect of our research will be the combination of RNAi technology with small molecule screens in the hope of isolating more specific drug targets for the Wnt pathway. Though identifying specific targets of small molecules is always a challenge, our approach of comparing and integrating information about specific phenotypes from the RNAi and the small molecule screens, should aid in making target identification faster. This approach will allow us to not only propose new testable hypotheses about the mechanisms of the regulators of the Wnt-signaling pathway, but also in drug discovery with relevance to treatment and prevention of Wnt pathway-related diseases.