Pulmonary TB remains a leading global health issue, but the current Bacille Calmette-Guérin (BCG) vaccine fails to control it effectively. Much effort has gone into developing safe and effective boost vaccine candidates for use after the BCG prime vaccination. To date, almost all the lead candidates are being evaluated clinically via a parenteral route. Abundant experimental evidence suggests that parenteral boosting with a virus-based vaccine is much less effective than respiratory mucosal boosting, because the former fails to activate a type of T cell capable of rapidly transmigrating into the airway luminal space in the early phase of the Mycobacterium tuberculosis infection. The next few years will determine whether parenteral boosting with some of the lead vaccine candidates, particularly the protein-based vaccines, improves protection in humans over that by BCG. Much effort is needed to develop respiratory mucosal boost vaccines and to identify the reliable immune protective correlates in humans.