Clinical and experimental evidence indicate that PTD results from four primary pathogenic mechanisms: activation of the maternal or fetal HPA axis; amniochorionic-decidual or systemic inflammation; decidual hemorrhage; and, pathologic distention of the myometrium. Each of these four pathways has a distinct epidemiological and clinical profile, and unique biochemical and biophysical pathways initiating parturition, but shares a common final biochemical pathway involving myometrial activation and stimulation, and enhanced genital tract protease activity promoting PPROM and cervical change. Traditional methods of predicting women at risk relying on obstetrical history or symptoms and epidemiological risk factors are neither sensitive nor specific. Recent approaches to predicting PTD, including sonographic measurement of cervical length and biochemical assays for hCG, cytokines, fFN, MMPs, estrogens, and CRH, are more sensitive than traditional methods. Moreover, given the heterogeneous, interactive etiopathogeneses of PTD, multiple biochemical markers should not only increase sensitivity and specificity, but also permit the detection of the relative contribution of each pathogenesis to the overall risk of PTD.