More than one century after the discovery of their etiological agents, tuberculosis and leprosy remain as major health threats for humans, and the molecular mechanisms that lead to the development of both diseases are poorly understood. The elucidation of these mechanisms, and especially those allowing for the mycobacteria to systemically disseminate, should facilitate the development of new prophylactic and/or therapeutic strategies. This review is focused on the routes that Mycobacterium tuberculosis and Mycobacterium leprae may use to disseminate within the human body, and the potential roles played by recently characterized adhesins in this process.