The advent of trastuzumab and other human epidermal growth factor receptor 2 (HER2)-directed therapies has revolutionized the treatment of metastatic HER2-positive breast cancer, leading to prolonged survival and appreciable clinical benefit for a substantial subset of patients. Previously, in a retrospective study at our institution, we observed that nearly 10% of patients achieved a durable complete remission (DCR) following a combination of HER2-directed therapy and cytotoxic chemotherapy. We are currently expanding this study to include patients who were treated since the initial introduction of trastuzumab. From our ongoing study, we present a selected case series of three patients with metastatic HER2-positive breast cancer who achieved a DCR. It is theorized that metastatic HER2-positive breast cancer may be potentially curable in certain patients with favorable clinicopathological and molecular factors, which the patients within our case series mostly demonstrate. These include de novo presentation, estrogen receptor (ER)-negative status, limited disease burden, and absence of deleterious gene or pathway mutations. More research is needed in order to incorporate these findings into clinical practice.