The application of MS constitutes one of the biggest technological advances introduced to protein research. It offers an unbiased platform to analyse global protein expression and holds potential in facilitating novel insights. As recently highlighted in a scientific statement of the American Heart Association55; it is anticipated that proteomics research will further our understanding of mechanisms of CVD with one important aspect being the elucidation of ECM composition in healthy and diseased cardiovascular tissues. To achieve this goal, bioinformatics approaches should be applied for interpreting the protein datasets and extract the biologically relevant information. Undoubtedly, the amount of data generated by proteomics represent an analytical challenge. In this regard, special attention should be paid to ECM fragments as they hold potential for two purposes: from a diagnostic perspective, they leak from tissues and when released into the blood stream can be used as biomarkers for CVD. Secondly, since many ECM fragments are biologically active, they not only hold potential as therapeutic targets but also as modifiable therapeutic agents—to date an underexplored avenue of cardiovascular medicine.