Breast cancer is the second leading cause of cancer death in women in the United States. While mammography and breast magnetic resonance imaging (MRI) improve detection of early disease, there remains an unmet need for biomarkers for risk stratification, early detection, prediction, and disease prognosis. Sera from patients with breast cancer contain specific autoantibodies (AAb) to tumor antigens that develop as part of the natural immune response to cancer-associated changes in protein structure and expression. The recent development of proteomic tools for AAb detection, including protein microarrays, reverse-phase protein immunoblots, and phage display have identified a number of potential AAb biomarkers for clinical development. Immune response signatures have been identified that are highly specific, but with variable sensitivities for cancer detection. This review focuses on the detection and application of AAb signatures as biomarkers for breast cancer detection and monitoring.