US investigations of school-based outbreaks of 2009 pandemic influenza A (H1N1) virus infection characterized influenza-like illness (ILI) attack rates, transmission risk factors, and adherence to nonpharmaceutical interventions. We summarize seven school-based investigations conducted during April-June 2009 to determine what questions might be answered by future investigations. Surveys were administered 5-28 days after identification of the outbreaks, and participation rates varied among households (39-86%) and individuals (24-49%). Compared with adults (4%-10%) and children aged <4 years (2%-7%), elementary through university students had higher ILI attack rates (4%-32%). Large gatherings or close contact with sick persons were identified as transmission risk factors. More participants reported adherence to hygiene measures, but fewer reported adherence to isolation measures. Challenges included low participation and delays in survey initiation that potentially introduced bias. Although school-based investigations can increase our understanding of epidemiology and prevention strategy effectiveness, investigators should decide which objectives are most feasible, given timing and design constraints.