A systematic review was undertaken to examine all available evidence to develop and support clinical recommendations regarding the use of fulvestrant (Faslodex((R))) as systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women. MEDLINE, EMBASE, American Society of Clinical Oncology Annual Meeting proceedings, San Antonio Breast Cancer Symposia proceedings, and the Cochrane Library were searched through to April of 2008 for reports of randomized controlled trials that met established inclusion criteria. Four relevant Phase III trials were available for inclusion based on established criteria. Three of four Phase III superiority trials found no significant difference between fulvestrant and control, either anastrozole or exemestane, across efficacy and safety endpoints following prior endocrine therapy failure, with two trials further confirming non-inferiority of fulvestrant to anastrozole retrospectively. Fulvestrant can therefore be considered as alternative therapy to anastrozole or exemestane in postmenopausal women with locally advanced or metastatic breast cancer that has recurred on prior adjuvant endocrine therapy or progressed on prior endocrine therapy for advanced disease. There are, however, important methodological concerns across reviewed trials that should be taken under consideration as they may limit the strength of such a conclusion.