Breast cancer remains the most frequently diagnosed female cancer, accounting for 23 % of the total cancer cases and 14% of the cancer deaths. Extensive research has been done for subtyping breast cancer at molecular and genetic level and to determine various clinical, pathological and molecular factors for selection of treatment modalities and prognostication of the disease at the diagnosis. Triple-negative breast cancer (TNBC) is a heterogeneous group of breast tumors simply defined by the absence of estrogen and progesterone receptors and human epidermal growth factor receptor 2, encompassing the molecular subtypes of basal-like and the more recently defined claudin-low group. TNBC accounts for 10–20 % of all invasive breast cancers and has been found to be associated with African American race, younger age, higher grade and mitotic index, and more advanced stage at diagnosis. In TNBC patients, the 5-year survival rate is much lower than other forms of breast cancer, and clearly, new approaches are needed to improve the clinical outcome for these patients. Molecular analysis of tumors has identified many genes that are overexpressed in TNBC, which could be exploited as tumor antigens and potential vaccine candidates. Currently, the most common tumor antigens exploited in cancer immunotherapy are up-regulated self-proteins, such as HER2. While mutated epitopes are recognized as foreign “neo-antigens” by the immune system eliciting Type I response, epitopes derived from non-mutated self-antigens are more likely to trigger Th2 polarizing cytokines such as IL-10 and IL-6 that inhibit CTL proliferation and function. Recently attempts have been made to identify Th1-selective epitopes from non mutated self-antigens that could elicit a “neo-antigen” like response. The Th1-selective epitopes, when used in a vaccine, can elicit unopposed Type I immunity and are effective in preventing cancer growth in pre-clinical models. If Th2 inducing epitopes from the same protein are included in a vaccine, Th2 cells elicited by immunization will abrogate the anti-tumor effect of Th. Therefore, the vaccines composed only of Th1 inducing epitopes may allow unrestricted expansion of both Th1 and CTL. Th1 selective non-mutated antigen vaccines may be effective in preventing disease recurrence and progression. If the antigens are expressed early in oncogenesis, vaccines could have utility in prevention. Novel and more promising target antigens for preventive cancer vaccines may be identified from careful analyses of molecular alterations such as overexpressed genes in premalignant and/or malignant tissues discovered through the TCGA and other cancer genomics projects. Some of the genes overexpressed in premalignant and malignant lesions, but not in normal tissues, could be immunogenic and capable of eliciting protective anti tumor immune responses. High priority candidate genes can be selected from the list of overexpressed genes by employing a systematic approach, for example, based on differential expression patterns between premalignant or malignant lesions vs. normal tissues, functional roles in physiologic or oncogenic signaling pathways, and immunogenicity prediction and in vitro screening processes. Once candidate target proteins are selected, peptide based vaccines may be designed following the scoring methods developed by Disis et al. [5] and can be preclinically tested for in vivo immunogenicity and tumor preventive efficacy in relevant models. These kind of rational design strategies may help expedite the discovery and development of an efficacious cancer vaccine for prevention of various cancers including cancer of the breast.