There is accumulating epidemiologic and experimental evidence that intrauterine or postnatal infection with Ureaplasma species is a significant risk factor for adverse pregnancy outcomes and complications of extreme preterm birth such as bronchopulmonary dysplasia and intraventricular hemorrhage. In a cohort of very low birth weight infants, Ureaplasma spp were detected by culture or polymerase chain reaction in respiratory secretions, blood, or cerebrospinal fluid of almost half of the subjects, suggesting that this organism is the most common pathogen affecting this population. This review summarizes the evidence supporting the hypothesis that Ureaplasma-mediated inflammation in different compartments (intrauterine, lung, blood, or brain) during a common developmental window of vulnerability contributes to preterm labor and lung and brain injury. Appropriate methods for detecting these fastidious organisms and potential strategies to prevent or ameliorate the effects of Ureaplasma infection are discussed.