Despite unmet needs for cardiovascular biomarkers, few new protein markers have been approved by the US Food and Drug Administration for the diagnosis or screening of cardiovascular diseases. Mass spectrometry-based proteomics technologies are capable of identifying hundreds to thousands of proteins in cells, tissues, and biofluids. Proteomics may therefore provide the opportunity to elucidate new biomarkers and pathways without a prior known association with cardiovascular disease; however, important obstacles remain. In this review, we focus on emerging techniques that may form a coherently integrated pipeline to overcome present limitations to both the discovery and validation processes.