Success in reducing tuberculosis (TB) incidence in developed nations has created a paradoxical problem for researchers. In many countries, there are too few cases to support the research necessary to maintain and accelerate the decline. We describe an approach to applied TB research that supports and focuses efforts of researchers at 21 academic, clinical, and governmental sites in two countries. The Tuberculosis Epidemiologic Studies Consortium (TBESC), funded by the Centers for Disease Control and Prevention (CDC) and by outside sources, conducts programmatically relevant epidemiologic, behavioral, economic, laboratory, and operational research for TB prevention and control. Our experience may serve as a model for other types of applied health care research.