Background: The first 20 years of publication of Cancer Epidemiology, Biomarkers & Prevention occurred during a period of increased attention to health disparities and advances in knowledge about their determinants. Yet, despite clear documentation of disparities and advanced understanding of determinants, we have made little headway in reducing disparities at the population level. Multilevel models, such as one produced by the Centers for Population Health and Health Disparities (CPHHD), hold promise for understanding the complex determinants of cancer disparities and their interactions as well as translating scientific discoveries into solutions. The CPHHD model maps across a range of scientific disciplines, from the biological to the social, each with its own disciplinary language and methods. The ability to work effectively across disciplinary boundaries is essential to framing comprehensive solutions. Methods: After briefly characterizing the current state of knowledge about health disparities, we outline three major challenges faced by disparities researchers and practitioners and offer suggestions for addressing these challenges. Results: These challenges are how to consider race and ethnicity in disparities research, how best to translate discoveries into public health solutions to cancer disparities, and how to create a research environment that supports the successful execution of multilevel research. Conclusions: Attention to all three of the challenges outlined above is urgently needed to advance our efforts to eliminate cancer disparities. Impact: Addressing the challenges outlined above will help to eliminate disparities in the future.