Recent years have witnessed an increased appreciation of the extent and relevance of strain-to-strain variation in Mycobacterium tuberculosis. This paradigm shift can largely be attributed to an improved understanding of the global population structure of this organism, and to the realisation that the various members of the M. tuberculosis complex (MTBC) harbour more genetic diversity than previously realised. Moreover, many studies using experimental models of infection have demonstrated that MTBC diversity translates into significant differences in immunogenecity and virulence . However, linking these experimental phenotypes to relevant clinical phenotypes has been difficult, and to date, largely unsuccessful. Nevertheless, emerging high-throughput technologies, in particular next-generation sequencing , offer new opportunities, and have already lead to important new insights. Given the complexity of the host-pathogen interaction in tuberculosis, systems approaches will be key to define the role of MTBC diversity in the fight against one of humankind's most important pathogens.