The currently available vaccine for tuberculosis (TB) is ineffective in developing countries. We need to understand the pathogenesis of TB in those countries and how it differs from the pathogenesis of TB in wealthy countries, to facilitate the design and interpretation of clinical trials of new vaccine candidates that are now available. We show here that these geographical differences parallel the strikingly different immunology and bacterial growth curves seen in animal models after high-dose and low-dose challenge with M. tuberculosis (Mtb). We consider this point in the light of recent insights into the multiple pathways used by the immune response to control M. tuberculosis and the susceptibilities of these pathways to regulation and suppression. There are important implications for the screening, testing, and likely success of vaccine candidates.