Trastuzumab has shown significant efficacy in HER2-overexpressing breast cancers and is approved for patients whose tumors carry this abnormality, both in the metastatic and in the adjuvant settings. However, several issues about its optimal use remain unresolved. Many breast cancer patients with HER2 overexpression do not respond to initial therapy with trastuzumab (Herceptin(®)), and a vast majority of these develop resistance to this monoclonal antibody within one year. This review discusses the molecular mechanisms leading to the development of trastuzumab resistance, including circulating HER2 extracellular domain, loss of PTEN, activation of alternative pathways (e.g. IGFR), and receptor-antibody interaction block. Additionally, the possibility of exploring these aberrations as therapeutic targets that potentially overcome resistance to trastuzumab is highlighted.