There is an urgent need to identify and develop a new generation of therapeutic agents and systemic therapies targeting the Estradiol (E₂)/Estrogen Receptor (ER) signaling in breast cancer. In this regard, new information on the mechanisms of E₂/ER function and/or cross-talk with other pro-survival cascades should provide the basis for the development of other "ideal" anti-E₂ therapies with the intent to enhance clinical efficacy and reduce side effects or both. Our very recent assessment of the mechanisms by which cancer-associated increased lipogenesis and its inhibition alters the E₂/ER signaling discovered that Fatty Acid Synthase (FASN), the enzyme catalyzing the terminal steps in the de novo biosynthesis of long-chain fatty acids, differentially modulates the state of sensitivity of breast and endometrial cancer cells to E₂-stimulated ER transcriptional activation and E₂-dependent cell growth and survival: 1) Pharmacological inhibition of FASN activity induced a dramatic augmentation of E₂-stimulated ER-driven gene transcription, while RNAi-mediated silencing of FAS gene expression drastically lowered E₂ requirements for optimal activation of ER transcriptional activation in breast cancer cells. Conversely, pharmacological and RNAi-induced inhibition of FASN worked as an antagonist of E₂- and Tamoxifen (TAM)-dependent ER transcriptional activity in endometrial adenocarcinoma cells; 2) Pharmacological and RNAi-induced inhibition of FASN synergistically enhanced E₂-mediated down-regulation of ER protein and mRNA expression in breast cancer cells, while specific FASN blockade resulted in a marked down-regulation of E₂-stimulated ER expression in endometrial cancer cells; and 3) FASN inhibition decreased cell proliferation and cell viability by promoting apoptosis in hormone-dependent breast and endometrial cancer cells. In this review we propose that, through a complex mechanism involving the regulation of MAPK/ER crosstalk as well as critical E₂-related proteins including the Her-2/neu (erbB-2) oncogene and the Cyclin-Dependent Kinase Inhibitors (CDK_is) p21^WAF1/CIP1 and p27^Kip1, a previously unrevealed connection exists between FASN and the genomic and non-genomic ER activities in breast and endometrial cancer cells. From a clinical perspective, we suggest that if chemically stable FASN inhibitors or cell-selective systems able to deliver RNAi targeting FASN gene demonstrate systemic anticancer effects of FASN inhibition in vivo, additional preclinical studies to characterize their anti-breast cancer actions should be of great interest as the specific blockade of FASN activity may also provide a protective means against endometrial carcinoma associated with TAM-based breast cancer therapy.