Metastatic HER2-positive breast cancer remains a significant clinical challenge with a poor prognosis. The introduction of anti-HER2 therapies has significantly improved survival in early and advanced stages. However, patients with metastatic HER2-positive breast cancer eventually experience progression due to de novo or acquired resistance. This review article comprehensively analyzes the current management of metastatic HER2-positive breast cancer, addressing the complexities in determining the optimal HER2-targeted therapy sequence.