It is 1999, during the American Society of Clinical Oncology (ASCO) Annual Meeting, and the plenary session is dedicated to the randomized studies that have failed to demonstrate a meaningful benefit from high-dose therapy in breast cancer. The aromatase inhibitors are showing real promise, though. They have already become the agents of choice in postmenopausal women with estrogen receptor (ER) –positive metastatic disease after tamoxifen failure, and are challenging tamoxifen as the gold standard in metastatic disease. Trastuzumab is US Food and Drug Administration (FDA) –approved as a single agent in HER-2 overexpressed metastatic disease, and an indication for combination therapy is imminent. Pamidronate has just been registered for bone metastases. Docetaxel is now the reference cytotoxic in metastatic disease, but paclitaxel and capecitabine also have US FDA indications in this setting. Although lacking a US FDA indication in breast cancer, vinorelbine (registered for non–smallcell lung cancer), gemcitabine (registered for pancreatic cancer and non–small-cell lung cancer), pegylated liposomal doxorubicin (registered for Kaposi’s sarcoma and submitted for ovarian cancer), and mitoxantrone (registered for hormone-refractory prostate cancer and acute nonlymphocytic leukemia) are also in use in third-, fourth-, and fifth-line therapy. In the adjuvant setting, doxorubicin and cyclophosphamide are the mainstay of current adjuvant regimens, paclitaxel has just received an accelerated approval for use after standard doxorubicin-containing therapy and, after years of use in the rest of the world, epirubicin has finally hit the US market. Since 1999, though, fulvestrant and zoledronic acid are the only new agents to be US FDA–approved for breast cancer therapy (http://www.fda.gov). The relative lack of new drug registrations does not reflect a lack of progress, however. The turn of the century marked the start of a profound shift in attitude regarding management of metastatic disease. Improvements in both efficacy and tolerability of systemic therapy have been achieved by modifying drug formulation and/or dose schedule; liposomal encapsulation can modify both the pharmacokinetics and tissue distribution of active agents, oral formulations permit continuous exposure of the tumor to the cytotoxic, tumor-specific enzymes can be harnessed to selectively activate prodrugs in order to spare normal tissues from toxicity, and the traditional 3-weekly dosing schedule is now the exception rather than the rule.