Patients with a tumor presenting amplification of the HER2 gene are currently proposed trastuzumab (herceptin) and this has greatly changed their outcome. However, a number of HER2-positive cancers show intrinsic or acquired resistance to trastuzumab and there are clear indications that they form a heterogeneous group of tumors. A paper in this issue of Breast Cancer Research addresses this heterogeneity at the genomic level.