Preterm birth rates continue to rise in the United States despite the advent of tocolytic agents and the identification of risk factors for preterm birth, such as vaginal infection and a shortened cervix. Although improvement in gestational-age-related survival of preterm infants has occurred as a result of the use of antenatal corticosteroids, neonatal surfactant therapy, and regionalization of perinatal care, there has been no reduction in the incidence of preterm birth. Recently, investigators have appreciated that the etiology of preterm birth is heterogeneous, perhaps accounting for one reason for the failure of current interventions to improve pregnancy outcome. Both abnormal maternal hormonal homeostasis and intrauterine inflammatory responses appear to contribute to a significant proportion of the cases of preterm birth, and the interaction of the maternal endocrine and immunologic systems may contribute to the pathophysiology of this condition. An important modulator of endocrine and immune function is perceived emotional and social stress. Maternal stress has been strongly associated with preterm birth, but the links between maternal stress and resultant aberrations of maternal endocrine and immune function remain difficult to quantify and investigate. However, new insights into the role of perceived maternal stress on gestational length suggest that specific interventions to alleviate stress could contribute to an increase in gestational length and a decrease in the risk for preterm birth. This review addresses the role of maternal stress on the regulation of maternal hormone and inflammatory responses and how aberrations in these systems may lead to preterm birth.