Human epidermal growth factor receptor 2 (HER2/neu or ErbB2)-positive breast cancers comprise 15%-20% of all breast cancers. The most common manifestation of HER2-positive breast cancer at mammography or US is an irregular mass with spiculated margins that often contains calcifications; at MRI, HER2-positive breast cancer may appear as a mass or as nonmass enhancement. HER2-positive breast cancers are often of intermediate to high nuclear grade at histopathologic analysis, with increased risk of local recurrence and metastases and poorer overall prognosis. However, treatment with targeted monoclonal antibody therapies such as trastuzumab and pertuzumab provides better local-regional control and leads to improved survival outcome. With neoadjuvant treatments, including monoclonal antibodies, taxanes, and anthracyclines, women are now potentially able to undergo breast conservation therapy and sentinel lymph node biopsy versus mastectomy and axillary lymph node dissection. Thus, the radiologist's role in assessing the extent of local-regional disease and response to neoadjuvant treatment at imaging is important to inform surgical planning and adjuvant treatment. However, assessment of treatment response remains difficult, with the potential for different imaging modalities to result in underestimation or overestimation of disease to varying degrees when compared with surgical pathologic analysis. In particular, the presence of calcifications at mammography is especially difficult to correlate with the results of pathologic analysis after chemotherapy. Breast MRI findings remain the best predictor of pathologic response. The authors review the initial manifestations of HER2-positive tumors, the varied responses to neoadjuvant chemotherapy, and the challenges in assessing residual cancer burden through a multimodality imaging review with pathologic correlation. © RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.