The HIV epidemic has led to large increases in the frequency of smear-negative pulmonary tuberculosis, which has poor treatment outcomes and excessive early mortality compared with smear-positive disease. We used a combination of systematic review, document analysis, and global expert opinion to review the extent of this problem. We also looked at policies of national tuberculosis control programmes for the diagnosis of smear-negative pulmonary tuberculosis to assess their coverage, identify the diagnostic difficulties, and find ways to improve the diagnosis of this type of tuberculosis, with a focus on resource-constrained settings with high HIV infection rates. We propose that the internationally recommended algorithm for the diagnosis of smear-negative pulmonary tuberculosis should be revised to include HIV status, severity of AIDS and tuberculosis, and early use of chest radiography in the decision tree. Increased use of promising methods of diagnosis such as sputum liquefaction and concentration and increased availability of fluorescence microscopy should be explored and encouraged. Culturing of sputum in resource-constrained settings with high HIV infection rates should also be encouraged, existing facilities should be made full use of and upgraded, and effective quality-assurance systems should be used. Innovative ways to address human resources issues involved in addressing the diagnostic difficulties are also needed. The development of rapid, simple, and accurate tuberculosis diagnostic tools with applicability at point of care and remote location is essential. To achieve these goals, greater political commitment, scientific interest, and investment are needed.