Understanding the specific biological functions of Crk and CrkL has been challenging because deletion of either gene from the mouse germline results in embryonic or early postnatal lethality, and because both proteins function very similarly in biochemical and molecular assays. Previously, we generated mutant mice carrying floxed alleles of Crk and CrkL allowing conditional mutation using the CRE system. Ablation of both Crk and CrkL in neuronal precursor cells demonstrated that they provide specific overlapping functions downstream of Reelin in the control of radial neuronal migration during brain development. This project represents an expansion and new direction of this study to investigate the role of Crk and CrkL in a range of cell types in vitro and in vivo. Establishment of the Crkfl/fl/CrkLfl/fl strain of mice as well as Crkfl/fl and CrkLfl/fl strains provides a unique and powerful experimental tool. Three specific aims were addressed that focus on the role of Crk and CrkL in fibroblast growth (Aim 1), in other cell types in vivo and in vivo (Aim 2) and in cell transformation and tumor growth (Aim 3). Comparison of phenotypes obtained from Crkfl/fl/CrkLfl/fl cells and tissues with those from Crkfl/fl and CrkLfl/fl mice provided detailed understanding of how Crk and CrkL play both overlapping and individually unique functions in various cells and tissues. Understanding both conserved and specific functions of Crk and CrkL in various cell types will enable us to address fundamental questions in birth defects and cancer.