Over the past several decades there has been growing evidence of the increase in incidence rates, morbidity, and mortality for a number of health problems experienced by children. The causation and aggravation of these problems are complex and multifactorial. The burden of these health problems and environmental exposures is borne disproportionately by children from low-income communities and communities of color. Researchers and funding institutions have called for increased attention to the complex issues that affect the health of children living in marginalized communities–and communities more broadly–and have suggested greater community involvement in processes that shape research and intervention approaches, for example, through community-based participatory research (CBPR) partnerships among academic, health services, public health, and community-based organizations. Centers for Children’s Environmental Health and Disease Prevention Research (Children’s Centers) funded by the National Institute of Environmental Health Sciences and U.S. Environmental Protection Agency were required to include a CBPR project. The purpose of this article is to provide a definition and set of CBPR principles, to describe the rationale for and major benefits of using this approach, to draw on the experiences of six of the Children’s Centers in using CBPR, and to provide lessons learned and recommendations for how to successfully establish and maintain CBPR partnerships aimed at enhancing our understanding and addressing the multiple determinants of children’s health.