Breast cancer is the most common cancer in women worldwide with rising prevalence. The human epidermal growth factor receptor 2 (HER2) is crucial to the biological behavior and pathogenic mechanism of breast cancer. Approximately 45%- 55% of all subtypes of breast cancer have low expression of HER2, which are classified as HER2 immunohistochemistry staining 1+ or 2+ and in situ hybridization (ISH) negative. Although in most cases, HER2 low expression (HER2-low) breast cancer is still classified as HER2 negative or triple negative in clinical practice, HER2-low differs from HER2 not detected (HER2-0) breast cancer not only in HER2 expression levels, there are also differences in terms of estrogen receptor (ER) status, primary tumor volume, lymph node involvement, and pathologic complete response (pCR) following neoadjuvant therapy and disease-free survival (DFS). In clinical trials targeting early-stage HER2-low breast cancer, the NSABP B-31 and N9831 trials demonstrated the possibilities for breast cancer patients to benefit from adjuvant trastuzumab therapy; however, in phase III prospective randomized controlled study NSABP B-47, trastuzumab did not alter invasive disease-free survival (iDFS), 5-year interval without distant recurrence, or overall survival (OS) in patients with HER2-low breast cancer. Recent years have seen the emergence of clinical trials for targeted treatments for advanced HER2-low breast cancer, focusing mostly on trastuzumab, lapatinib, and antibody-drug conjugate (ADC), such as trastuzumab emtansine (T-DM1), DS-8201 (also known as trastuzumab deruxtecan, T-DXd, Enhertu), and SYD985. Phase III trial CALGB9840 demonstrated a lack of therapeutic effect of trastuzumab and a narrow therapeutic window that could not be overcome by changing the dose of lumretuzumab in HER2 non-over-expressed breast cancer, respectively. Two randomized phase III trials (EGF30001 and EGF100151) both found that receiving lapatinib did not improve progression-free survival (PFS) in patients with HER2-low breast cancer. T-DM1 sensitivity was initially observed in patients with HER2-low breast cancer in the single-arm phase II studies 4258g and 4374g, but results were still uncertain because of the small number of patients. The phase III clinical study DESTINY-Breast04 proved the safety and efficacy of DS-8201 (5.4 mg/kg) in HER2-low metastatic breast cancer. The phase I clinical trial proved the efficacy and safety of 1.2 mg/kg SYD985 intravenously in HER2-low breast cancer. Additionally, there are currently ongoing clinical trials for several novel anti-HER2 therapeutics, including novel ADC drugs (RC48-ADC, ARX788, A166, etc.), bispecific antibodies (KN026, ZW25, ertumaxomab, etc.), and breast cancer vaccines (nelipepimut-S, GP2, AE37, etc.). In this paper, we will review the major clinical trials of targeted therapies for HER2-low breast cancer. [ABSTRACT FROM AUTHOR]