HER2 overexpression is observed in 15—20% of patients with invasive breast cancer (BC) and is associated with poor prognosis. Trastuzumab is the first drug that has HER2 as its target. The addition of trastuzumab to standard chemotherapy significantly improved the survival of BC patients. Pertuzumab is a humanized monoclonal antibody against the epitope of subdomain II of the HER2 extracellular domain and a dimerization receptor inhibitor. Dual anti-HER2-blockade was investigated in the phase III CLEOPATRA trial comparing a combination of docetaxel, trastuzumab, and pertuzumab with a control combination of docetaxel, trastuzumab, and placebo in first-line therapy for advanced BC. Adding pertuzumab increased median relapse-free survival from 12.4 to 18.7 months and median overall survival from 40.8 to 56.5 months with no significant toxicity or negative impact on quality of life. In patients who had previously treated with anti-HER2-drugs, trastuzumab-emtansine (T-DM1), an antibody-drug conjugate comprising the monoclonal antibody trastuzumab and the cytotoxic agent DM1, showed high efficacy. The TH3RESA trial showed that T-DM1 had an advantage over a treatment of physician’s choice in intensively pretreated BC patients. The phase III EMILIA trial demonstrated that T-DM1 was superior to capecitabine and lapatinib in second-line treatment for advanced BC in both relapse-free (9.6 months versus 6.4 months), and overall (30.9 months vs. 25.1 months) survival rates. The current MARIANNE trial is intended to evaluate a combination of pertuzumab and T-DM1 in the first-line treatment of HER2-positive advanced breast cancer.