Apnea of prematurity (AOP) is found in >50% of premature infants and is almost universal in infants who are <1000 g at birth. The literature clearly defines clinically significant apnea in infants (breathing pauses that last for >20 seconds or for >10 seconds if associated with bradycardia or oxygen desaturation), but there is no consensus about the duration of apnea, the degree of change in oxygen saturation, or severity of bradycardia that should be considered pathologic. Although caregivers are able to respond successfully to apnea events with drugs (as well as physical and mechanical interventions) in the NICU, it remains unproven whether such interventions have any long-term effects. One of the most effective drugs, caffeine citrate, is currently labeled for short-term use only and within a limited gestational-age population. Clinicians often use off-label drugs that have been approved for gastroesophageal reflux disease, which is common in premature infants, with the belief that such treatments also have an impact on AOP, although this link has never been demonstrated. Key treatment issues include (1) lack of standardization for definition, diagnosis, and treatment of AOP, (2) unproven benefit of intervention, (3) lack of real-time data documenting AOP events, (4) unevaluated sustained treatment improvement at 7 days or later, (5) failure to address confounding conditions, (6) unsubstantiated AOP-gastroesophageal reflux disease relationship, and (7) undetermined role of AOP affecting long-term neurodevelopmental outcomes. In addressing study-design issues, the pulmonary group identified (1) key questions about neonatal apnea, (2) methodologic requirements for study, (3) appropriate outcome measures, and (4) ethical considerations for future studies. This article describes a sample framework for the study of apnea in neonates and identifies future research needs. Plenary-session discussion points are also listed.