The HER2 receptor is currently one of the flagship therapeutic targets in clinical oncology. Trastuzumab, an antibody targeting HER2, has become a foundation of care in women with HER2-positive breast cancer. However, many women with metastatic breast cancer do not respond to trastuzumab-based therapy. One possible source of trastuzumab resistance is the presence of truncated forms of HER2 in the tumor. Numerous studies suggest that detection of truncated HER2 in the tumor should result in modification of the classical therapeutic approach. Recent development of several promising compounds brings hope that a generation of novel therapeutic modalities against HER2-positive cancers will be delivered in the future.