The identification of easily detectable biomarkers for active tuberculosis (TB) is a global health priority. Such biomarkers would be of particular value in childhood TB, which poses greater diagnostic challenges than adult TB. Serum antibodies can be detected by simple formats that provide extremely rapid results. However, attempts to develop accurate serodiagnostic tests for TB have been unsuccessful. Whereas antibody responses to mycobacterial antigens in adult TB have been studied extensively and reviewed, the same cannot be said for serologic data in pediatric populations. Here we appraise studies on serological responses in childhood TB and discuss findings and limitations in the context of the developing immune system, the age range, and the spectrum of TB manifestations. We found that the antibody responses to mycobacterial antigens in childhood TB can vary widely, with sensitivities and specificities ranging from 14% to 85% and from 86% to 100%, respectively. We conclude that the limitations in serodiagnostic studies of childhood TB are manifold, thereby restricting the interpretation of currently available data. Concerns about the methodology used in published studies suggest that conclusions about the eventual value of serodiagnosis cannot be made at this time. However, the available data suggest a potential adjunctive value for serology in the diagnosis of childhood TB. Despite the difficulties noted in this field, there is optimism that the application of novel antigens and the integration of those factors which contribute to the serological responses in childhood TB can lead to useful future diagnostics.