Pregnancy associated plasma protein-A (PAPP-A), originally discovered as a glycoprotein found in the serum of pregnant women, is emerging as a potential biomarker of plaque instability. It is produced by the syncytiotrophoblasts of the placenta and circulates in the form of an approximately 500 kDa heterotetramer. In addition, PAPP-A is present in the sera of men and non-pregnant women at much lower levels in the form of a homodimer, and is produced by a number of different non-placental cell types, including fibroblasts, vascular endothelial cells, and vascular smooth muscle cells. The identification of PAPP-A as a member of the metzincin metalloproteinase superfamily, its synthesis by cell types involved in atherogenesis, and its role in insulin-like growth factor-I regulation has led to the hypothesis that PAPP-A is involved in atherosclerotic plaque progression and instability. Serum PAPP-A may be a biomarker for the detection of vulnerable, unstable plaque. Although early reports appear to validate this hypothesis, adoption of PAPP-A as a clinical cardiac biomarker will need assay standardization and further clinical validation. The clinical validation will require a large and diverse patient population, a clearly defined and uniform diagnostic strategy, incorporation of multiple biomarkers in addition to PAPP-A, and measurement of outcomes data.