mTOR activation is frequently observed and associated with worst prognosis for the human ovarian cancer patients. Different mTOR inhibitors are currently in human ovarian cancer clinical trials. However, role of mTOR signaling in the pathogenesis of ovarian cancer is unknown. We observed frequent alterations in genes (LKB1, TSC1, TSC2, and PTEN) involved in mTOR signaling in human ovarian serous cancer (HOSC). LKB1 (Liver Kinase B1) gene was deleted in up to 70% of patients. Loss of LKB1 protein and concurrent increase in mTOR activity was observed in 52% of HOSC tissue samples and 70% of the HOSC cell lines. Conditional deletion of Lkb1 (Lkb1cko) in mouse ovarian surface epithelial (OSE) cells caused OSE papillary hyperplasia but no tumors. Simultaneous loss of Lkb1 and Pten lead to the development of ovarian serous cancer in 100% animals (Lkb1ckoPtencko). Ovarian cancer in Lkb1ckoPtencko mice expressed typical markers (WT1, Pax8, and ERa) used for HOSC patients. Rapamycin, a well-known inhibitor of mTOR, treatment suppressed OSE papillary hyperplasia and loss of either TSC1 or TSC2 gene (Tuberous Sclerosis 1 and 2, upstream regulators of mTOR signaling) phenocopies Lkb1cko phenotype. Collectively, we have shown importance of LKB1-mTOR signaling in HOSC pathogenesis. Currently, we are conducting preclinical trials using these mouse models to develop better therapeutic treatments for human ovarian cancer patients.