Addressing health disparities has been a national challenge for decades. The National Institutes of Health-sponsored Centers for Population Health and Health Disparities are the first federal initiative to support transdisciplinary multilevel research on the determinants of health disparities. Their novel research approach combines population, clinical, and basic science to elucidate the complex determinants of health disparities. The centers are partnering with community-based, public, and quasi-public organizations to disseminate scientific findings and guide clinical practice in communities. In turn, communities and public health agents are shaping the research. The relationships forged through these complex collaborations increase the likelihood that the centers' scientific findings will be relevant to communities and contribute to reductions in health disparities.