Proteomics is the study of functions, structures, and interactions of the entire set of proteins that shape and regulate the life. Advances in mass spectrometry-based proteomic technologies have opened the new avenue to identify and quantify thousands of proteins, post-translational modification (PTM) and their system network regulating various biological and physiological functions. Personalized proteomics starts to impact the development of precision medicine by facilitating discovery of protein biomarkers, molecular signature of disease subtype and response to treatment of individual patients. Combing proteomics with the long standing success of genomics, proteogenomics has been rapidly advanced as an emerging tool for full delineation of genomic-to-proteomic network associated with disease. In this talk, I will share our experiences and the long-term journey from the development of proteomics techniques to their utility in discovering new biology and identify opportunity for cancer diagnosis and precision medicine. A specific example will be demonstrated on how proteogenomics provides new insight on the molecular signature and pathogenesis of early stage lung adenocarcinomas and breast cancer in Taiwan. We delineated endogenous and exogenesis mutational signatures as well as the proteogenomic hallmarks of tumor progression of our non-smoking patients. Most excitingly, proteomics-informed classification demonstrated differentiation of the diverse clinical trajectories of patients within early stages. The opportunity, follow up plans and challenges for pursuing new strategies for precision medicine will be discussed. To implement the proteomics tools for their potential clinical utility, I will also share our recent development of a global phosphoproteomics system (GPS) strategy and a highly streamlined single cell proteomics jointly developed with Dr. Hsiung-Lin Tu.