It is critical to determine if the fallopian tubal secretory epithelial cell (FTSEC) is the cell-of-origin for the majority of high-grade serous ovarian and peritoneal carcinomas. Little experimental evidence exists to support this novel paradigm shift. We propose to develop experimental models to demonstrate that FTSEC is indeed the cell of origin for high-grade serous carcinomas. Furthermore, we plan to examine in vivo the key events responsible for the initiation and propagation of precursor tubal lesions to invasive ovarian and peritoneal serous carcinomas. Our animal models, which accurately recapitulate the human disease, constitute great tools for defining the key roles that tumor cells in the distal fallopian tube play in tumor initiation and resistance to chemotherapy. Furthermore, they provide us with unique, relevant in vivo systems in which to screen novel molecularly targeted therapies as they become available. Data collected from these key animal models will be instrumental for the development of new methods for cancer prevention, early detection, and treatment. We remain hopeful that our research will have immediate clinical applications.