Although selective estrogen receptor modulators (SERMs), such as tamoxifen, or aromatase inhibitors (AIs), such as anastrozole, are the preferred endocrine treatment approach for most patients with hormone receptor-positive breast cancer, many patients progress despite this therapy or become resistant. Fulvestrant is a selective estrogen receptor down-regulator (SERD) that has demonstrated activity and efficacy in patients with hormone receptor-positive breast cancer previously untreated or treated with hormonal therapy. The efficacy of fulvestrant has been demonstrated in the neoadjuvant and metastatic settings, either alone or in combination with other therapies such as anastrozole or targeted drugs. Additionally, 500 mg of fulvestrant have been shown to be more effective than 250 mg, without significant differences in the toxicity profile. In this review, the unique mode of action of fulvestrant and the clinical data for different dosing regimens both alone or in combination with other drugs is critically assessed.