Multilevel interventions can be uniquely effective at addressing minority health and health disparities, but they pose substantial methodological, data analytic, and assessment challenges that must be considered when designing and applying interventions and assessment. To facilitate the adoption of multilevel interventions to reduce health disparities, we outline areas of need in filling existing operational challenges to the design and assessment of multilevel interventions. We discuss areas of development that address overarching constructs inherent in multilevel interventions, with a particular focus on their application to minority health and health disparities. Our approach will prove useful to researchers, as it allows them to integrate information related to health disparities research into the framework of broader constructs with which they are familiar. We urge researchers to prioritize building transdisciplinary teams and the skills needed to overcome the challenges in designing and assessing multilevel interventions, as even small contributions can accelerate progress toward improving minority health and reducing health disparities. To make substantial progress, however, a concerted and strategic effort, including work to advance analytic techniques and measures, is needed.