Tiffany A. Traina, MD; Vijayakrishna Gadi, MD, PhD, and Heather McArthur, MD, explore the current treatment landscape for HER2-positive metastatic breast cancer. They discuss standard of care therapies across lines, pivotal trial data, management of brain metastases, optimal sequencing strategies after, and emerging novel agents. Two patient cases help illustrate real-world decision-making.