Mycobacterium tuberculosis remains the most important bacterial pathogen of humans, resulting in approximately two million deaths per annum. Although tuberculosis (TB) is primarily a pulmonary infection, the bacteria can disseminate to seed virtually any organ and tissue where it may persist for decades. The mechanisms by which M. tuberculosis spreads from the original site of infection remain unclear. It is not known whether free bacteria, infected macrophages or other cell types are involved in this important trafficking process. Plasminogen (plg) is a main component of the human fibrinolytic system. Several bacterial pathogens of humans have the ability to bind plg on their surface which can then be converted to plasmin. Surface bound plasmin confers proteolytic activity to the bacterium allowing it to modify the in vivo host environment and enhance virulence. M. tuberculosis has been shown to bind plg. We have demonstrated, with both confocal microscopy and direct enzymatic assay, that M. tuberculosis binds human plg preferentially to that of the mouse, and no plasmin activity is detected following incubation in mouse plasma. Due to the low binding affinity of mouse plg to M. tuberculosis, a transgenic humanised plg+/+ mouse was created and infection of this strain revealed enhanced dissemination to the liver following a low dose aerosol infection. Furthermore, clinical isolates from cases of human extra pulmonary TB, have shown an increased ability to bind plg to the bacterial surface and on going research is currently trying to identify possible novel receptors on these strains. Improved knowledge of this important pathogenic process is not only essential to our understanding of TB, but may also lead to novel preventative and treatment strategies.