During the last decade our knowledge on estrogen action has been highly enriched by new data on their ability to exert rapid effects that are initiated at the membrane and activate a number of membrane related kinases and subsequently modify intracellular signaling cascades. One of the major targets of membrane initiated action of estradiol in a variety of cell types is actin cytoskeleton. Cytoskeletal modifications are of great importance since they can lead to changes in a wide range of cellular functions. More specifically estradiol has been shown to induce endothelial remodeling (Simoncini et al, 2006), axonal growth (Sanchez et al, 2009) and modulate cell migration of both normal (e.g. endometrial stromal cells) (Flamini et al, 2011) and cancerous (e.g. breast cancer cells) (Kampa et al, 2008, Sanchez et al, 2010) cells. Indeed in breast cancer, estrogens have been reported to induce actin cytoskeleton re-distribution that favors cell migration which is required for cancer cell invasion and metastasis. Their action occurs through membrane estrogen receptors that trigger specific signaling events, involving G proteins, small GTPases, src, FAK, cdc42 and N-WASP. Even though the nature of membrane estrogen receptor has not been fully elucidated, it has been shown both biochemically (Sanchez et al, 2010) and verified by our group by a transcriptome analysis that the membrane receptor involved in this cytoskeletal action is ERα (Kampa et al, 2012). Interestingly, this is not the only role for ERα, which has in its sequence an interesting motif (P295-T311) that is located between the D- (hinge) and E- (Ligand Binding Domain) regions, in the autonomous activation function AF-2a, and is considered as an important platform for various post-translational modifications and calmodulin binding. In fact a peptide corresponding to this motif (ERα17p) that could be liberated after the proteosomal degradation of ERα, we have equally found to induce rapid actin cytoskeleton re-arrangements and affect cell migration independently of the presence of ERα (Kampa et al, 2011) . This finding is very interesting since ERα bearing cells can affect the migration of ER negative cells and modulate one of the major problems of breast cancer, metastasis.