Tuberculosis was declared a global public health emergency in 1993. In 2003, only 45% of the world's estimated new smear-positive tuberculosis cases were detected-well below the 70% global case detection target set by the World Health Organization. The FIDELIS (Fund for Innovative DOTS Expansion Through Local Initiatives to Stop TB) initiative is a new global disease control initiative that has been developed to rapidly assess and implement innovative approaches to increase tuberculosis case detection. To date, 32 projects have been approved-covering approximately 378 million people in 13 countries-24 (75%) of which are in the world's 6 highest-burden countries. A wide range of target populations and interventions have been incorporated into successful FIDELIS projects. The FIDELIS initiative may serve as a model to discover best practices to address other urgent global public health problems.