Overexpression of HER2 is encountered in approximately 20% of invasive breast cancers. It is an independent adverse prognostic factor and, more importantly, it is currently the best predictive factor for the activity of trastuzumab, an anti-HER2 monoclonal antibody (MoAb), which has revolutionized the treatment of this breast cancer subgroup. Increasing knowledge of molecular pathways involving the HER family of growth factor receptors has paved the way toward new efficient targeted therapies. Herein, we will review the targeted therapies of clinical importance for HER2-positive breast cancer, which include anti-HER2 MoAbs and tyrosine kinase inhibitors that directly interfere at the receptor level. Clinicians are still facing many uncertainties concerning the optimal use of these new agents, and scientists are working on dissecting the mechanisms of resistance developed by HER2-positive cancer cells. Interesting perspectives in the treatment of HER2-positive breast cancer will be discussed. They consist of designing HER2 peptide-based vaccines, targeting downstream pathway molecules beyond the membrane receptor, and exploring synergistic antineoplasic strategies.