With the increasing number of long-term survivors of childhood cancer, there continues to be a critical need for development and implementation of evidence-based recommendations for clinical follow-up. In order to establish and maintain health-related follow-up guidelines, it is important to recognize the attributes of research from which the recommendations may be formulated. Issues including study design and clinical research methodology, completeness of long-term follow-up for the applicable study population, approaches for assessment of treatment-related exposures, methods utilized for ascertainment and characterization of outcomes, and recognition of potential modifiers of risk (e.g., demographic or treatment-specific factors) are all important considerations when evaluating the results of available research. For the future, greater attention will not only need to be given to further development and maintenance of recommendations for follow-up, but to the scientific evaluation of the recommendations to determine the subsequent impact on health status and quality of life among pediatric cancer survivors.