Simple SummaryThe development of drug resistance in HER2 targeted therapies poses a major challenge in breast cancer treatment. To address this challenge, researchers have adopted two main strategies: repurposing existing drugs to enhance their effectiveness and identifying new targets to broaden the range of therapeutic options. This review discusses current research efforts in these two areas, highlighting key points and challenges. By pursuing these strategies, researchers hope to improve treatment outcomes and overcome drug resistance, ultimately leading to better outcomes for patients with HER2-positive breast cancer.AbstractThe amplification of epidermal growth factor receptor 2 (HER2) is associated with a poor prognosis andHER2gene is overexpressed in approximately 15–30% of breast cancers. In HER2-positive breast cancer patients, HER2-targeted therapies improved clinical outcomes and survival rates. However, drug resistance to anti-HER2 drugs is almost unavoidable, leaving some patients with an unmet need for better prognoses. Therefore, exploring strategies to delay or revert drug resistance is urgent. In recent years, new targets and regimens have emerged continuously. This review discusses the fundamental mechanisms of drug resistance in the targeted therapies of HER2-positive breast cancer and summarizes recent research progress in this field, including preclinical and basic research studies.