Development of HER2-targeted therapy drugs, particularly trastuzumab, demonstrated significant improvement of clinical outcomes among HER2 positive breast cancer patients during the last two decades. The exact biological mechanism of HER2 gene amplification occurrence remains unsolved. HER2 gene amplification and/or HER2 protein overexpression are the primary predictors for selecting invasive breast cancer patients as candidates for anti-HER2 agent-based chemotherapy protocol. However, HER2-targeted therapy is not completely successful: as it is well-documented, only one half of HER2 positive breast cancer patients achieve a pathological complete response after such a precision therapy. In the past, various HER2 drug resistance mechanisms were proposed for explaining incomplete the efficacy with anti-HER2 drugs. Recent studies suggested that HER2 intratumoral heterogeneity (ITH) determined by a concomitant HER2 gene and protein analyses are a significant primary resistance mechanism to HER2-targeted therapy. Recent discovery of undocumented "nonclassic" HER2-positive tumor cells with the amplified HER2 gene but no HER2 protein overexpression redefined HER2 ITH. The HER2 ITH consists of two groups of tumor heterogeneity subtypes: (1) genetic ITH (a mixture of HER2 negative tumor cells and classic HER2 positive tumor cells) and (2) nongenetic ITH (a mixture of classic HER2 positive tumor cells and nonclassic HER2 positive tumor cells). The mechanism underlining these nonclassic HER2 positive tumor cells with the amplified HER2 gene, but no HER2 protein overexpression, is unknown. Investigation of impaired HER2 and/or protein translation in these tumor cells could lead to a further improvement of cancer therapy by identifying new therapeutic targets for patients with HER2 ITH.