The use of the C3HeB/FeJ mouse strain has a special signification in the field of experimental tuberculosis. The majority of the work for developing new drugs and vaccines was done using the C57Bl/6 and BALB/c mice. In these strains, lesions are characterized by the lack of a strong inflammatory response, and the scarcity of neutrophilic infiltration. Just the oposite to what is seen in lesions of active TB in humans. On the contrary, Mycobacterium tuberculosis challenge in the C3HeB/FeJ strain, does develop such scenario. This has a special relevance when looking after host-directed therapies, as the hallmark precisely is to stop the exagerated inflammatory response that makes possible the progression towards active TB. In this review we explain how hard was to settle the use of this model, because it was against pre-established dogma: neutrophiles had no role in the development of active TB; and extracellular bacillary growth takes place once liquefaction and cavitation is generated.