Despite the great progress made in the understanding of the biological behavior of certain types of invasive breast cancer, there is still no single histological or molecular classification that encompasses such diversity and accurately predicts the clinical course of distinct breast cancer subtypes. The long-lasting classification of breast cancer as HER2-positive vs. HER2-negative has recently come into question with the discovery of new antibody drug conjugates (ADC), which are proven to be remarkably efficient in treating HER2-low breast cancer. The HER2-low paradigm has challenged the traditional understanding of HER2 overexpression and emphasized the need for more robust HER2 testing in order to encompass HER2 intratumoral heterogeneity and spatial distribution more accurately. It is yet to be seen if low HER2 will remain merely a marker of HER2-equipped tumors targetable with ADCs or if distinctive molecular and phenotypic groups within HER2-low tumors will eventually be discerned.