Background: We describe the planning, recruitment, key challenges, and lessons learned in the development of a study of the evolution of nevi (moles) among children in a school setting. Methods: This population-based study of digital photography and dermoscopy of the child's back (overview, close-up, and dermoscopic images) and genetic specimens took place among fifth graders in the Framingham, Massachusetts School System. Schoolchildren and their parents completed baseline surveys on sun protection practices, sunburns, and past ultraviolet exposures, including summer and vacation experiences. Results: Prestudy outreach was conducted with children, parents, nurses, administrators, and pediatricians. Of the 691 Framingham families with a fifth grader (aged 10-11), 443 consented to complete surveys and undergo digital photography and dermoscopy during the school's routine scoliosis testing. Of the 443 families providing consent, 369 agreed to genetic testing. We identified key factors to consider when implementing school-based studies: (a) pilot studies to demonstrate feasibility, (b) inclusion of school administration and parents, (c) grassroots approach with multiple contacts, and (d) embedding research studies within preexisting school health services. Conclusions: Launching an observational study within the school environment required an academic/school collaboration across numerous disciplines including dermatology, epidemiology, genetics, medical photography, school health, community health education, and most notably, the need for the presence of a full-time study nurse in the school. A large school system proved to be an excellent resource to conduct this first prospective study on the evolution of moles in US schoolchildren. The key challenges and lessons learned may be applicable to other investigators launching school-based initiatives. (Contains 2 figures and 3 tables.)