Preterm labor leading to preterm delivery (<37 weeks’ gestation) affects approximately 5–7% of live births in developed countries, but significantly higher in developing countries. Prematurity due to preterm birth (PTB) accounts for around 28% of neonatal mortality worldwide. Approximately 45–50% of PTBs are idiopathic or spontaneous, 30% are related to preterm rupture of membranes, and another 15–20% are attributed to medically indicated or elective preterm deliveries. The rate of spontaneous PTB is also increasing and the exact cause is still unclear. Generalized approaches in screening for high risk status of preterm labor and interventions have failed to reduce PTB rates. PTB presents a clinical dilemma due to etiologic, pathophysiologic and genetic heterogeneities. Racial disparity in PTB rates observed in the US further complicates its understanding. PTB is a complex phenotype and is not initiated by a single etiologic agent. Etiologic factors operate through multiple pathophysiologic pathways, and these pathways include highly overlapping biomarkers and molecular factors creating pathophysiologic heterogeneities. In this article, the current understanding of PTB pathophysiology is reviewed and the need for a much broader approach in research, analysis and interpretation of data is explained, where environmental and race/ethnicity specific risk factors may dictate specific pathways leading to PTB. Recent data on amniotic fluid biomarkers and maternal and fetal genetic variants, which indicate huge disparity between races in the US, are also reviewed. These data suggest that gene–gene interactions and gene–environmental interactions produce distinct pathophysiologic pathways with respect to an individual's genetic make-up and environmental risk exposure. Current strategies of high risk screening and intervention measures may not be generalized, and a more individualized approach may be required to understand PTB and its prevention.