By 2050, ovarian cancer deaths are projected to exceed 350,000 annually, a 70% increase from 2022. Of these, 70% will be high-grade serous ovarian carcinoma (HGSC), the most aggressive subtype. Understanding HGSC is crucial for improving patient outcomes, but research has been hindered by a lack of recurrent mutations aside from TP53 and challenges related to the homologous recombination deficiency of HGSC, which can lead to significant genome loss. In my studies, I demonstrate that tubal epithelial (TE) organoids from the mouse uterine tube can be used in combinatorial screening to identify HGSC drivers and cell of origin. Using CRISPR knockout libraries, we found that Map2k4 mutations primarily form papillary tumor phenotypes, while Nf1 mutations lead to mesenchymal phenotypes. Map2k4 mutations were more sensitive to paclitaxel and resistant to trametinib. Additionally, TE organoid models closely reflect their in vivo counterparts, with SLC1A3+ cells more likely to form organoids and exhibit ciliation. These findings highlight the potential of TE organoid models for studying HGSC genetic drivers and the cell of origin. Overall, I demonstrate the potential of this system for use in future human studies, particularly in exploring spontaneous mutations caused by tumor promoting environmental factors. These findings could lead to the development of a more thorough diagnostic and prognostic pipeline and database that help monitor and improve patient survival.