Understanding the mechanisms of disease responsible for the syndrome of preeclampsia as well as early risk assessment is still a major challenge. The concentrations of circulating proteins in maternal blood such as placental growth factor, soluble vascular endothelial growth factor receptor-1 and soluble endoglin are altered weeks before the onset of clinical symptoms of the syndrome. Recently, other proteins in maternal serum, such as activin A, inhibin A, PAPP-A, and PP13 have been suggested to be of value in first trimester risk assessment. Since preeclampsia is a syndrome, it seems unlikely that a single test will predict all forms of preeclampsia. This realization has led to the formulation of a new conceptual framework suggesting that a combination of markers (biochemical and/or biophysical) may be required to conduct comprehensive risk assessment for the syndrome.