Proteins and peptides are well-documented as useful marker adjuncts to cardiovascular clinical decision-making. Most markers measured derive from a defined, stable proprotein region of their respective gene. However, a neglected portion of preproproteins known as the signal peptide (SP) is also present in the circulation and may also present as a measurable marker. SPs were assumed to be degraded intracellularly after directing secretion, but a small, growing body of evidence is identifying SPs as not being degraded within and without cells. In this article, evidence for the persistence of SPs after translation is presented and their role as potential cardiovascular biomarkers is discussed.