Estrogen and selective estrogen receptor modulators (SERMs) differentially impact endometrial and breast cancer cell function, however, the biological basis of these differences is not established. Deregulated cell adhesion to the extracellular matrix, cell movement and invasion are related to several disorders, such as endometriosis, endometrial and breast cancer metastasis. Remodeling of the actin cytoskeleton is required to achieve cell adhesion and movement. Estrogen receptor (ER) regulates actin and cell membrane remodeling through extra-nuclear signaling cascades. The aim of the present study was to characterize the effects of raloxifene (RAL), tamoxifen (TAM) or of 17β-estradiol (E2) with or without RAL or TAM on ER+T47-D breast cancer cell and on endometrial cell line Ishikawa or human endometrial stromal cells (ESC) cytoskeletal remodeling, migration and invasion. Our findings show that, when given alone, RAL induces a weak actin cytoskeleton remodeling in breast cancer cells, with the formation of specialized cell membrane structures implicated in cell motility and interaction with the extracellular matrix. However, in the presence of physiological amounts of estradiol, that potently drives breast cancer cell cytoskeletal remodeling and motility, RAL displays a powerful inhibitory effect on estrogen-promoted cell migration and invasion. These actions are plaid through an interference of RAL with an extra-nuclear signaling cascade involving G proteins and the RhoA-associated kinase, ROCK-2, linked to the recruitment of the cytoskeletal controller, moesin. Hence, in the presence of E2, RAL acts as an ER antagonist on a set of cellular events implicated with the process of breast cancer migration and metastasis. Furthermore, we show that administration E2 and TAM to Ishikawa or to ESC also results in remodeling of actin fibers and cell membrane. This is linked to rapid phosphorylation on moesin and enhanced migration and invasion of normal and Ishikawa cells. On the contrary RAL alone does not result in moesin activation or actin remodeling in endometrial cells. When endometrial cells are exposed to E2 in the presence of TAM or RAL, both SERMs interfere with the recruitment of moesin, with the remodeling of the cytoskeleton, and with cell movement and migration induced by E2. The differential actions of E2, TAM and RAL are linked to a distinct modulation of the extra- nuclear signaling of ER to G proteins and to the Rho-associated kinase. These findings increase our understanding of the actions of estrogen and SERMs in breast cancer and endometrial cells and highlight potential molecular targets to interfere with the estrogen-related altered cell adhesion encountered in endometrial disorders or breast cancer progression and/or metastasis induced by estrogens in postmenopausal women.