Metastatic breast cancer (MBC) is an incurable disease. The goal of treatment is mainly palliative to improve quality of life by the control of disease (in terms of disease free survival [DFS]) as long as possible, and to treat symptoms with fewer side effects. The gene c-erb B2 or neu or HER2 is amplified in 20-25% of breast cancers. This amplification is associated with a more aggressive disease and a poor prognosis. Patients, carrying a HER2-positive MBC, benefit from new therapies targeting the HER2 receptor. These treatments have shown their efficacy as single agent, and have a synergistic effect with chemotherapy. There is a more toxicity profile in comparison with that of chemotherapy. In first line metastatic disease, treatment should include a combination based on trastuzumab and chemotherapy. After disease progression with trastuzumab-based therapy, rechallenging Trastuzumab in combination with chemotherapy is a reasonable option. After a second progression with trastuzumab, a combination based on lapatinib plus Capecitabine (or other chemotherapy if Capecitabine was previously used) should be proposed; the combination based on lapatinib and trastuzumab is reasonable. Inclusion in clinical trials must continue to improve outcomes for our patients.