The treatment of patients with metastatic breast cancer that has progressed despite previous anthracycline- and taxane-based therapy is a challenge for oncologists. Several agents, including vinorelbine, gemcitabine, pemetrexed, and particularly capecitabine, have been evaluated in this setting, either alone or in combination with other cytotoxic agents. The efficacy of many of these agents has not yet been clearly established in this setting, as the majority have been evaluated in a limited number of patients and predominantly in single-center trials. Furthermore, some agents with clinically meaningful activity are often associated with significant toxicity, particularly myelosuppression and neuropathy, while less toxic agents/regimens often exchange improved tolerability for reduced activity. Capecitabine, an oral chemotherapeutic, is the agent that has been evaluated most extensively in this setting. A large, phase II trial (n = 163) conducted in North America demonstrated a disease control rate of 63%, including an objective response rate of 20%, median time to disease progression of 3.0 months, and median survival of approximately 1 year. Adverse events were typically mild to moderate in intensity and could be controlled with treatment interruption or, if necessary, dose adjustment to each individual's tolerable dose. Data recently reported from three other large trials in taxane-pretreated patients have revealed similar efficacy and tolerability. Together, these four trials show that single-agent capecitabine, in a population of 500 patients, consistently produced clinically meaningful efficacy, including median survival of approximately 1 year, with a favorable safety profile. Myelosuppression and alopecia were particularly rare. In addition, the oral administration of capecitabine, which enables convenient, patient-oriented therapy, makes it an attractive treatment for patients. Based primarily on the results of the pivotal trial, capecitabine received regulatory approval as treatment for anthracycline- and taxane-pretreated (paclitaxel-pretreated in the U.S.) metastatic breast cancer. In light of the confirmatory results of subsequent large trials, capecitabine is now considered a reference treatment in this setting, as no other agent has consistently demonstrated such high efficacy in as large a patient population.