Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that accounts for up to 40% of all endometrial cancer-related deaths. Recent whole-exome sequencing studies have revealed HER2/neu amplification in 27-44% of USC patients, supporting HER2 as an attractive pathway for target therapies based on monoclonal antibodies or tyrosine kinase inhibitors. Preclinical studies and a recently published prospective randomized trial with trastuzumab in combination with chemotherapy demonstrated promising results with anti-HER2-targeted therapies in advanced and recurrent USC patients. In contrast, single-agent trastuzumab or tyrosine kinase inhibitors (i.e., lapatinib) were unable to demonstrate significant clinical activity and/or durable tumor growth inhibition. Combinatorial therapies may represent novel, highly effective therapeutic strategies to overcome inborn or acquired resistance to HER2/neu-targeted therapies in HER2-amplified USC patients. This study presents a comprehensive review of the mechanisms of USC resistance to HER2-targeted therapies and potential strategies to overcome it.