Multi-level multi-component (MLMC) strategies have been recommended to prevent and reduce childhood obesity, but results of such trials have been mixed. The present work discusses lessons learned from three recently completed MLMC interventions to inform future research and policy addressing childhood obesity. B’more Healthy Communities for Kids (BHCK), Children’s Healthy Living (CHL), and Health and Local Community (SoL) trials had distinct cultural contexts, global regions, and study designs, but intervened at multiple levels of the socioecological model with strategies that address multiple components of complex food and physical activity environments to prevent childhood obesity. We discuss four common themes: (i) How to engage with community partners and involve them in development of intervention and study design; (ii) build and maintain intervention intensity by creating mutual promotion and reinforcement of the intervention activities across the multiple levels and components; (iii) conduct process evaluation for monitoring, midcourse corrections, and to engage stakeholder groups; and (iv) sustaining MLMC interventions and its effect by developing enduring and systems focused collaborations. The paper expands on each of these themes with specific lessons learned and presents future directions for MLMC trials.