Summary: The confirmation of the HER2-low paradigm is expected to have a major impact in breast oncology. About half of all breast cancers harbor HER2-low expression, which can be targeted with the anti-HER2 antibody–drug conjugate trastuzumab deruxtecan (T-DXd), leading to a relevant survival benefit in the metastatic setting. Given this observation, treatment algorithms for both hormone receptor–positive and triple-negative breast cancer are expected to significantly evolve in the next future. Several challenges, however, remain in the interpretation of HER2-low expression related to its biological role, its pathologic diagnosis, and the definition itself of HER2-low. In this article, we recapitulate the current knowledge on HER2-low breast cancer, discussing whether it should be considered a distinct subtype, how it should be implemented in the clinic, and how its definition may evolve in the coming years with the evolution of our clinical and translational knowledge.