The estrogen receptor(ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, posttranslational modification of ER, deregulation of ER coactivators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K/AKT/mammalian target of rapamycin(m TOR), Mitogen activated kinase(MAPK)/ERK, fibroblast growth factor receptor, insulin-like growth factor-1 receptor; alterations in cell cycle and apoptotic machinery; Epigenetic modificationincluding dysregulation of DNA methylation, histone modification, and nucleosome remodeling; and altered expression of specific micro RNAs. Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the m TOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important publications cited in Pub Med, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at Clinical Trials.gov. We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies. The estrogen receptor (ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, posttranslational modification of ER, deregulation of ER coactivators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K / AKT / mammalian target of rapamycin (m TOR), Mitogen activated kinase (MAPK) / ERK, fibroblast growth factor receptor, insulin-like growth factor- receptor; alterations in cell cycle and apoptotic machinery; Epigenetic mod Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the m TOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important signaling publications in Pub Med, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at Clinical Trials.gov. We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies.