The introduction of antiendocrine agents with differing mechanisms of action now mandates the design of rational sequential hormonal regimens for breast cancer. The aromatase inhibitors (AIs), including the nonsteroidal compounds anastrozole and letrozole and the steroidal compound exemestane, are important alternatives or adjuncts to the antiestrogen agent tamoxifen in postmenopausal women with hormone receptor-positive breast cancer in the first-line management of advanced disease and in the adjuvant treatment of early-stage disease. These and other endocrine agents, including the newer estrogen receptor antagonist fulvestrant and also tamoxifen itself, have not been extensively evaluated within the context of hormonal sequencing. Based on a retrospective analysis of data from 3 phase III trials, patients treated with fulvestrant in the first- or second-line hormonal management of advanced breast cancer may derive further clinical benefit from subsequent treatment with an endocrine agent from another class. The need for prospective investigation of post-AI hormonal therapy is intensifying as a result of the increasing clinical use of the AIs. Sophisticated sequencing regimens designed to exploit different mechanisms of action have the potential to confer greater clinical benefit than the historical approach of selecting the agent with the next highest single-agent clinical activity upon disease progression.