Tuberculosis (TB) is one of the oldest diseases known to man and is caused by Mycobacterium tuberculosis. Still tuberculosis causes over 1.5 million deaths annually. The currently used live attenuated vaccine strain Mycobacterium bovis BCG has proven to be ineffective and does not protect against pulmonary TB in adults. Additionally, over the last decades multi-, extensively- and even totally drug-resistant M. tuberculosis strains have been emerging, so there is an urgent need for new TB intervention strategies. A better understanding of host–pathogen interactions underlying mycobacterial pathogenicity would enhance the development of more effective anti-TB therapies. In our laboratory we use a biochemical, genetic and cell biological approach to study the interaction of pathogenic mycobacteria with their host. As a model organism we use the fish pathogen Mycobacterium marinum, which grows faster and can be used at a medium biosafety level (BSL-2). However, we also have a fully functional BLS-3 facility to confirm our findings for M. tuberculosis. Central in our research is the bacterial cell surface, as many of the host –pathogen interactions take place at this interface.