Up to one-third of the global population is thought to harbour M. tuberculosis infection, but only a fraction of infected persons progress to active TB disease. It is unclear why only some infected individuals progress to TB disease, while others do not. Using systems immunology we dissected the immunobiology underlying progression from M. tuberculosis infection to active disease in a longitudinal study, and developed transcriptomic and proteomic correlates of TB risk that identify progressors before diagnosis of TB disease is possible. Predicting disease progression in asymptomatic individuals provides an opportunity for chemotherapeutic intervention and potential prevention of M. tuberculosis transmission.