Improvements in the characterization of human tumors have resulted in better survival rates for cancer patients. However, less progress has been made in the development of clinical tools to monitor the course of the disease. Tumor markers have not had a broad acceptance in the clinical community, because the few that are known are organ rather than tumor specific. Proteomics biomarker discovery research is usually a brute-force effort, and suffers from lack of reproducibility and high biological sample complexity. There is need for proteomics hypothesis-driven biomarker discovery approaches that incorporate technology advances with understanding cancer at the molecular level. I propose a biomarker discovery approach that combines exploiting the tumor cell’s communication with its microenvironment and with the rest of the organism, with a proteomics method designed to specifically measure secreted proteins (the ‘secretome’). My hypothesis is that signaling pathways are altered during tumorigenesis, and that these alterations are translated into protein differential secretion, which potentially can be used to discover secreted markers. The strategy proposed entails generating breast cancer secretome signatures and mine them to discover secreted pathway-based biomarkers. There is great hope that the discovery of pathway-based biomarkers in breast cancer secretomes will facilitate individualized diagnostics and treatment of breast cancer patients.