Tuberculosis remains a major global health threat. Nearly one-third of the world population infected with Mycobacterium tuberculosis, the etiologic agent of tuberculosis. M. tuberculosis is a typical and most successful intracellular pathogen. The pathogen can evade and manipulate the host immune response. Insights into the interplays between the pathogen and the host was pivotal to develop more sophisticated diagnosis methods and control measures to tuberculosis. No single model can address the full spectrum of this extraordinarily successful pathogen. Multiple models are urgently needed to explore diverse facets of this human being scourge. Zebrafish-M. marinum model was increasingly recognized as an ideal system for preliminary studies. Some key findings emerging from this model were summarized in this paper, such as the interactions between host and M. marinum when the bacterium invades and the contribution of the virulence determinants of M. marinum such as Erp, Esx-1, pmiA, Mel and KasB. Discoveries from different models will be complementary and conducive to find clues to eradicate Mycobacterium tuberculosis.