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Abstract: Numerous factors play a part in health disparities. Although health disparities are manifested at the level of the individual, other contexts should be considered when investigating the associations of disparities with clinical outcomes. These contexts include families, neighborhoods, social organizations, and healthcare facilities. This paper reports on health disparities research as a multilevel research domain from the perspective of a large national initiative. The Centers for Population Health and Health Disparities (CPHHD) program was established by the NIH to examine the highly dimensional, complex nature of disparities and their effects on health. Because of its inherently transdisciplinary nature, the CPHHD program provides a unique environment in which to perform multilevel health disparities research. During the course of the program, the CPHHD centers have experienced challenges specific to this type of research. The challenges were categorized along three axes: sources of subjects and data, data characteristics, and multilevel analysis and interpretation. The CPHHDs collectively offer a unique example of how these challenges are met; just as importantly, they reveal a broad range of issues that health disparities researchers should consider as they pursue transdisciplinary investigations in this domain, particularly in the context of a large team science initiative. [Copyright &y& Elsevier]