Critical questions about cancer prevention, care, and outcomes increasingly require research involving large patient populations and their care delivery organizations. The Cancer Research Network (CRN) includes 11 integrated health systems funded by the National Cancer Institute (NCI) to conduct collaborative cancer research. This article describes the challenges of constructing a productive consortium of large health systems, and explores the CRN’s responses. The CRN was initially funded through an NCI cooperative agreement in 1999 and has since received a second 4-year grant. Leadership and policy development are provided through a steering committee, subcommittees, and an external advisory committee. The CRN includes integral and affiliated research projects supported by a Scientific and Data Resources Core. Three characteristics of the CRN intensified the general challenges of consortium research: 1) its members are large health systems with legitimate concerns about confidentiality of data about enrollees, providers, and the organization; 2) CRN research projects often generate highly sensitive data about quality of care; and therefore 3) each participating organization wants a strong voice in CRN direction. CRN experience to date confirms that a consortium of health systems with internal research capacity can address a range of important cancer research questions that would be difficult to study in other venues. The advantages and challenges of consortium research are explored, with suggestions for the development, execution, and management of multisystem population laboratories.