The role of endocrine therapy in early as well as advanced breast cancer cannot be overrated. Long-term tamoxifen exposure (5 years) in the adjuvant setting has been shown to be effective not only in improving relapse-free and overall survival but also in reducing the incidence of contralateral cancers. Promising results have been achieved in breast cancer prevention with use of antiestrogens. Novel aromatase inhibitors and inactivators have been found superior to conventional treatment in metastatic disease and are currently being evaluated in the adjuvant setting to improve relapse-free and overall survival. If potential health hazards from estrogen deprivation with regard to cardiovascular disease as well as bone metabolism can be addressed, adjuvant endocrine therapy may include such drugs in the future. However, while endocrine therapy of breast cancer has become more and more important in the clinic, the major problems in hormonal therapy are primary and acquired resistance to endocrine manipulations. The causes for endocrine resistance and possible ways to delay or avoid this phenomenon are only allusively understood. Elucidation of the mechanisms underlying endocrine resistance in vivo represents the key to improve our treatment strategies. Due to intense use of in vitro models and animal systems, many potential mechanisms of endocrine resistance have been described; however, our understanding of the problem of drug resistance in vivo remains limited. Hopefully, ongoing programs on translational research in the neoadjuvant, adjuvant, and palliative settings will provide information that will improve our understanding of the biology of endocrine resistance in vivo and, thus, provide us with a better rationale to improve early as well as late endocrine therapy in breast cancer patients. The present publication summarizes the state of the art with respect to endocrine resistance.