: In this issue of Clinical and Vaccine Immunology, Siev and colleagues present an evaluation of antibody responses to four immunodominant proteins of Mycobacterium tuberculosis in patients with HIV-associated pulmonary tuberculosis (TB) in South Africa (M. Siev, D. Wilson, S. Kainth, V. O. Kasprowicz, C. M. Feintuch, E. Jenny-Avital, and J. J. Achkar, 21:791-798, 2014, doi:http://dx.doi.org/10.1128/CVI.00805-13). This commentary discusses the enormous need for simple point-of-care assays for tuberculosis (TB) diagnosis in patients with and without HIV coinfection in high-burden settings and considers the potential role of serological assays and the huge challenges inherent in developing and validating such assays.<br/>