Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of breast cancers, correlating with more aggressive disease and poorer prognosis. Historically, treatment involved chemotherapy combined with HER2-targeted monoclonal antibodies like trastuzumab and pertuzumab. However, resistance to these drugs remains a challenge. Antibody–drug conjugates (ADCs), such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have shown superior outcomes in HER2-positive and HER2-Low breast cancer. Despite this, resistance remains a problem, prompting research into better-tolerated and more effective therapies. T-DM1, the first FDA-approved ADC for HER2-positive breast cancer, has demonstrated improved progression-free survival and disease-free survival in clinical trials. However, resistance mechanisms include antigen-related, payload-related, internalization, lysosomal dysfunction, drug-efflux, cell cycle dependencies, and survival signaling pathway activation. T-DXd, with a higher drug-to-antibody ratio, has shown efficacy in HER2-Low breast cancer and is approved for metastatic cases. However, it carries risks of interstitial lung disease and other toxicities. New ADCs, such as disitamab vedotin (RC48), ARX788, trastuzumab duocarmazine (SYD985), BL-M0701, and zanidatamab zovodotin (ZW49), are under investigation. These agents aim to improve efficacy, reduce resistance, and enhance safety. Clinical trials are evaluating their safety, efficacy, and optimal dosing regimens. Future directions include site-specific conjugation methods, improved preclinical models, and combination therapies to overcome resistance and enhance treatment outcomes. These advancements highlight the potential of next-generation HER2-targeted ADCs to improve outcomes for patients with HER2-positive and HER2-Low breast cancer.Next-Generation HER2-Targeted Antibody–Drug Conjugates in Breast Cancer Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of breast cancers, correlating with more aggressive disease and poorer prognosis. Historically, treatment involved chemotherapy combined with HER2-targeted monoclonal antibodies like trastuzumab and pertuzumab. However, resistance to these drugs remains a challenge. Antibody–drug conjugates (ADCs), such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have shown superior outcomes in HER2-positive and HER2-Low breast cancer. Despite this, resistance remains a problem, prompting research into better-tolerated and more effective therapies. T-DM1, the first FDA-approved ADC for HER2-positive breast cancer, has demonstrated improved progression-free survival and disease-free survival in clinical trials. However, resistance mechanisms include antigen-related, payload-related, internalization, lysosomal dysfunction, drug-efflux, cell cycle dependencies, and survival signaling pathway activation. T-DXd, with a higher drug-to-antibody ratio, has shown efficacy in HER2-Low breast cancer and is approved for metastatic cases. However, it carries risks of interstitial lung disease and other toxicities. New ADCs, such as disitamab vedotin (RC48), ARX788, trastuzumab duocarmazine (SYD985), BL-M0701, and zanidatamab zovodotin (ZW49), are under investigation. These agents aim to improve efficacy, reduce resistance, and enhance safety. Clinical trials are evaluating their safety, efficacy, and optimal dosing regimens. Future directions include site-specific conjugation methods, improved preclinical models, and combination therapies to overcome resistance and enhance treatment outcomes. These advancements highlight the potential of next-generation HER2-targeted ADCs to improve outcomes for patients with HER2-positive and HER2-Low breast cancer.