The establishment of the National Institute of Health and Human Development Neonatal Research Network in 1986 was an acknowledgement by the medical community of the need to rigorously perform patient-oriented research in neonates. The limit of viability was being pushed below 26 weeks' gestation by physicians willing to try almost anything to save their extremely low gestational age patients and/or by parents who were willing to accept survival at almost any cost. Too often new treatments or procedures had become standard therapies before efficacy and/or safety had been evaluated. During its first 15 years, the Network has conducted randomized, controlled trials and prospective observational studies focused on such major neonatal issues as brain injury, neuroprotection, late-onset infection, bronchopulmonary dysplasia, severe hypoxic respiratory failure, postnatal growth and nutrition, and long-term neurodevelopmental outcome. This paper reviews the Network's investigative activities during that time, highlights some of the lessons learned in its attempts to identify clinically relevant outcomesthat would change clinical practice, and addresses future challenges.