Mutation leading to constitutive b-catenin activity are present in nearly all colon cancers and are essential for maintaining tumor growth. However, despite large efforts we lack efficient b-catenin inhibitors. We have taken an alternative approach, using large scale RNAi, CRISPR and CRISPRi loss of function screens to identify genes that are required for proliferation only in the context of aberrant b-catenin activity. We demonstrate the utility of combing these methodologies as a highly specific approach for identifying cell essential genes. Although this approach identified new targets for drug development, systematic characterization of genes that score in high throughput screens is still a major challenge. To overcome this hurdle, we developed an approach that allows CRISPR mediated pairwise knockouts and performed a double knockout screen of 13k combinations. This approach identified 375 combinations exhibiting greater or lesser than additive phenotypic effects indicating genetic interactions. Based on these experiments we identified new pathways associated with genes that are required for proliferation of b-catenin driven cancers and further validated these findings using high throughput proteomics. We demonstrate the utility of combing different methodologies for systematic understanding of gene function and develop new approaches for characterization of genes that score in these screens.