Human epidermal growth factor receptor 2 (HER2) is a tumor associated antigen over-expressed in 20-30% of cases of breast cancer. Passive immune therapy with HER2-directed monoclonal antibodies (mabs) has changed the natural history of this subset of breast tumors both in the localized and metastatic settings. The safety and efficacy of HER2 vaccines have been assessed in early phase clinical trials but to date clinically relevant results in late phase trials remain an elusive target. Here, we review the recent translational discoveries related to the interactions between the adaptive immune system and the HER2 antigen in breast cancer, results of published clinical trials, and future directions in the field of HER2 vaccine treatment development.