The management of human epidermal growth factor receptor (HER2)-positive breast cancer has improved over the past decade. However, despite improvements in systemic control, a substantial proportion of patients with advanced HER2-positive breast cancer suffer from central nervous system metastases and even intracranial progression after aggressive local treatment. There is paucity of data and no consensus on the systemic therapies for patients with intracranial progression. This review discusses both local and systemic treatments for HER2-positive breast cancer with brain metastases with a special focus on the response of central nervous system metastases. A recommended practical treatment algorithm to guide physicians in selecting the most appropriate anti-HER2 therapy for their patients is suggested.