The ovarian surface epithelium is the pelvic mesothelium overlaying the ovaries. It is the precursor of the common epithelial ovarian carcinomas. In contrast to carcinomas in other physiological sites, where normal tissues of origin are stably epithelial and their neoplastic derivatives undergo epithelio-mesenchymal transition (EMT), normal ovarian epithelial cells (OSE) undergo EMT in response to environmental influences while epithelial ovarian cancer cells maintain differentiated epithelial phenotypes. The present study examined the molecular mechanisms and possible physiologic basis for the propensity of OSE to undergo EMT. At ovulation, ovarian surface epithelial layer is disrupted and the displaced fragments trapped in the ovarian cortex or the ruptured follicles are exposed to EMT-inducing factors derived from follicular fluid, platelets, stromal and luteal cells. We hypothesized that EMT may be a homeostatic mechanism that permits displaced OSE to assume a stromal phenotype within the ovarian cortex. Previously we have reported that epidermal growth factor (EGF) in conjunction with hydrocortisone (HC) is the EMT-inducing factor of OSE as shown by changes to a fibroblast-like morphology and growth pattern, increased collagen type III deposition and reduced keratin expression. We now report that EGF also increased cell motility, enhanced activities of secreted pro-matrix metalloproteinase 2 and 9, and enhanced expression and activation of extracellular signal regulated kinase (Erk) and integrin-linked kinase (ILK). Increased ILK expression correlated with the phosphorylation of protein kinase B (PKB)/Akt and glycogen synthase kinase 3 (GSK-3) and increased expression of cyclin E and cdk2 kinase. EGF withdrawal resulted in a more epithelial morphology and reversal of the EGF-induced activation of signaling pathways and pro-MMP activity. In contrast, treatment of EGF-treated cells with specific inhibitors of PI3 kinase, Mek or ILK inhibited the inhibitor-specific pathways but had no effect on complementary compensatory Erk or ILK pathways respectively. The inhibitors caused suppression of EGF-induced migration and pro-MMP2/9 activities, but no change in the EGF-induced mesenchymal morphology. ILK-siRNA inhibited Akt phosphorylation, total Akt and reduced pro-MMP2/9 activities, but had no effect on Erk activation or cell morphology. These results indicate that the EGF-induced morphological and functional changes in OSE are controlled by distinct signaling mechanisms working in cohort. EMT of OSE that is displaced by ovulation likely permits their survival and integration within the stroma under an altered, fibroblast-like identity. Failure of such mechanism(s) may lead to the formation of epithelium-derived inclusion cysts, which are known to be the preferential sites of malignant transformation.