About 75% of all breast cancers are estrogen receptor(ER)-positive. They generally have a more favorable clinical behavior, prognosis, and pattern of recurrence, and endocrine therapy forms the backbone of treatment. Anti-estrogens(such as tamoxifen and fulvestrant) and aromatase inhibitors(such as anastrozole, letrozole, and exemestane) can effectively control the disease and induce tumor responses in a large proportion of patients. However, the majority of patients progress during endocrine therapy(acquired resistance) and a proportion of patients may fail to respond to initial therapy(de novo resistance). Endocrine resistance is therefore of clinical concern and there is great interest in strategies that delay or circumvent it. A deeper knowledge of the molecular mechanisms that drive endocrine resistance has recently led to development of new strategies that have the promise to effectivelyovercome it. Many resistance mechanisms have been described, and the crosstalk between ER and growth factor receptor signaling pathways seems to represent one of the most relevant. Compounds that are able to inhibit key elements of these pathways and restore endocrine sensitivity have been studied and more are currently under development. The aim of this review is to summarize the molecular pathophysiology of endocrine resistance in breast cancer and its impact on current clinical management. About 75% of all breast cancers are estrogen receptor (ER) -positive. They generally have a more favorable clinical behavior, prognosis, and pattern of recurrence, and endocrine therapy forms of the backbone of treatment. Anti-estrogens (such as tamoxifen and fulvestrant ), and aromatase inhibitors (such as anastrozole, letrozole, and exemestane) can effectively control the disease and induce tumor responses in a large proportion of patients. However, the majority of patients progress during endocrine therapy (acquired resistance) and a proportion of patients may fail to respond to initial therapy (de novo resistance). Endocrine resistance is therefore the fear of clinical concern and there is great interest in strategies that delay or circumvent it. A deeper knowledge of the molecular mechanisms that drive endocrine resistance has recently led to development of new strategies that have the promise to effectively achieve it. Many resistance mechanisms have been described, and the crosstalk between ER and growth factor receptor signaling pathways seems to represent one of the most relevant. Compounds that are able to inhibit key elements of these pathways and restore endocrine sensitivity have been studied and more are currently under development. The aim of this review is to summarize the molecular pathophysiology of endocrine resistance in breast cancer and its impact on current clinical management.