Multilevel interventions are those that affect at least two levels of influence—for example, the patient and the health care provider. They can be experimental designs or natural experiments caused by changes in policy, such as the implementation of the Affordable Care Act or local policies. Measuring the effects of multilevel interventions is challenging, because they allow for interaction among levels, and the impact of each intervention must be assessed and translated into practice. We discuss how two projects from the National Institutes of Health’s Centers for Population Health and Health Disparities used multilevel interventions to reduce health disparities. The interventions, which focused on the uptake of the human papillomavirus vaccine and community-level dietary change, had mixed results. The design and implementation of multilevel interventions are facilitated by input from the community, and more advanced methods and measures are needed to evaluate the impact of the various levels and components of such interventions