Several biomarkers associated with spontaneous preterm birth (PTB) have been discovered over the last decade. Many of these markers, such as cytokines, are associated with infection and inflammation. As such, these biomarkers represent biologically plausible candidates for assessing those at risk of PTB. However, in the early association studies of biomarker-pregnancy outcome, the geographic ancestry of subjects was not considered. Based on more recent data, it is becoming increasingly evident that these biomarkers, and a universal approach that uses a single biomarker, fail to provide adequate assessment of risk in all subjects. Rather, recent data support the conclusion that some markers associate in subjects of African descent and another nonoverlapping set associates in subjects of European descent. These data indicate that diagnostic or predictive tests will have to use different biomarkers for different sets of subjects. If this is true, it poses severe restrictions on how to predict outcome or perform tests of association, and may make it impossible to determine risk or provide proper intervention. An alternative is presented that, although not yet proven, may make it possible to use a common set of biomarkers and their relationships to assess risk.