Tissue fibrosis is a hallmark of most cases of cardiovascular disease (CVD) and includes modification and deposition of extracellular matrix (ECM). However, detailed studies on the cardiovascular ECM have been sparse due to the lack of analytical tools that facilitate comprehensive characterization of its components. In recent years, proteomics has been successfully applied to study the ECM, providing unprecedented insights into its biology and pathological remodelling.2–5 In the present review, we describe the utility of ECM proteomics as applied to cardiovascular research and the potential pitfalls. In addition, we highlight the means to overcome common proteomic challenges and present translational applications of proteomic datasets.