Tuberculosis (TB) remains one of the world’s major infectious diseases affecting nations with limited public health resources. Multidrug resistance development has seriously compromised therapeutic treatment choices. The pathology of latent TB shows evidence of a reservoir of Mycobacterium tuberculosis (Mtb) in the lungs of affected individuals. If the pathogen is contained by the immune system, no overt disease symptoms occur. The environmental and internal triggers leading to disease reactivation are not well understood. Proteomic investigations of blood plasma and sputum derived from subjects with active TB versus latent TB versus healthy individuals may yield new biomarkers and, when surveying larger longitudinally monitored cohorts, may discriminate infection outcomes in an endemic setting.