Considered threats to validity and generalizability of psychological research with pediatric populations and proposed ways to better understand and manage these problems. Variation due to characteristics of acute and chronic conditions (e.g., duration, severity, illness course), settings and referral patterns, family environmental characteristics, as well as investigators' decisions concerning criteria and recruitment limit inferences concerning the impact of pediatric conditions on psychological development and generalizability of findings. These problems call for an expanded use of replication, cross-center, population-based, and theory-driven research. Scientific progress will be made by increasing dialogues and collaboration among researchers concerning generalizability problems and improving research training in epidemiological methods, analysis of large-scale data sets, and meta-analysis.