The human epidermal growth factor receptors (HERs) are expressed abundantly in the human body. The tumorigenic potential of HER2/neu is linked to its overexpression, amplification or somatic mutation. The HER2 gene amplification leading to protein overexpression has been reported in 25–30% of breast cancers and 10–30% of gastric/gastroesophageal cancers. While HER2 is a well-documented predictive, prognostic, and therapeutic marker in breast and gastric/gastroesophageal cancers, its relevance has also been demonstrated in multiple other malignancies. In this article, we will conduct an extensive review of current data pertaining to HER2 amplification, overexpression, or mutation in cancers other than breast and gastric cancers.