In patients with breast cancer, current systemic therapies with CNS penetration mainly target the human epidermal growth factor receptor (HER2), such as tyrosine kinase inhibitors (e.g., laptinib, neratinib, and tucatinib), monoclonal antibodies (e.g., trastuzumab), and antibody–drug conjugates (e.g., trastuzumab-emtansine, and trastuzumab-deruxtecan). This evidence concerns the gene ERBB2 and breast cancer.