Breast cancer is the most common cancer globally, with HER2-positive breast cancer accounting for 15-20% of cases. HER2-targeted therapies like trastuzumab and pertuzumab have improved patient outcomes, but drug resistance remains a significant challenge. The PI3K/AKT signaling pathway is frequently aberrantly activated in HER2-positive breast cancer and plays a key role in drug resistance. This review summarizes the molecular alterations in HER2-positive breast cancer, the relationship between HER2 overexpression and the PI3K/AKT pathway, and the mechanisms of resistance to HER2-targeted therapies. It highlights the importance of the HER2-AKT pathway in tumor progression and resistance, and discusses current therapeutic strategies targeting this pathway. The review also emphasizes the need for further research to develop more effective treatments for HER2-positive breast cancer, particularly in overcoming resistance.Breast cancer is the most common cancer globally, with HER2-positive breast cancer accounting for 15-20% of cases. HER2-targeted therapies like trastuzumab and pertuzumab have improved patient outcomes, but drug resistance remains a significant challenge. The PI3K/AKT signaling pathway is frequently aberrantly activated in HER2-positive breast cancer and plays a key role in drug resistance. This review summarizes the molecular alterations in HER2-positive breast cancer, the relationship between HER2 overexpression and the PI3K/AKT pathway, and the mechanisms of resistance to HER2-targeted therapies. It highlights the importance of the HER2-AKT pathway in tumor progression and resistance, and discusses current therapeutic strategies targeting this pathway. The review also emphasizes the need for further research to develop more effective treatments for HER2-positive breast cancer, particularly in overcoming resistance.