Tuberculosis (TB) ranks as the second cause of death from an infectious disease worldwide after HIV. Archaeogenetics and evolutionary scenario for the Mycobacterium tuberculosis complex (MTBC) are in favor of a long-term interaction between tuberculosis and humans, predating the Neolithic period, contrary to the traditional belief. If tuberculosis evolved as a human pathogen in Africa and has spread outside Africa about more than ten-thousand years ago, its life history traits have been shaped by the immune system. Numerous studies described a variety of human susceptibility factors to TB, suggesting that MTBC strains have evolved different ways to overcome this system. However, the results of these studies reveal some inconsistencies even within populations. The temporally varying history of epidemics and ever-varying genetic diversity of pathogens and strains could easily contribute to blur out signal of selection in our human genome. Palaeomicrobiology gives the opportunity to genotype ancient TB strains circulating in past populations. Accessing ancient human pathogens allows us to a better understanding of infectious agents over a longer time scale and confrontation with the dynamic of modern TB strains. Nevertheless, we have to consider tuberculosis as a multifactorial disorder in which environmental factors interact tightly with human and pathogen genetic.