The HEALTHY trial was designed to take a primary prevention approach to risk factors for type 2 diabetes in youth, primarily obesity. The study involved over 6,000 students at 42 middle schools across the U.S. Half received an integrated intervention program of components addressing the school food environment, physical education, lifestyle behaviors, and promotional messaging. The intervention was designed to be more comprehensive than previous efforts, and the research was amply funded. Although the primary objective of reducing the percentage of overweight and obesity in schools that received the intervention program, as compared with control schools, was not obtained, key secondary outcomes indicated an intervention effect. In retrospect, senior investigators involved in the study's design, conduct, and analysis discuss weaknesses and strengths and offer recommendations for future research efforts that address prevention of childhood obesity from a public health perspective.