Tuberculosis (TB) is a chronic inflammatory disease caused by the pathogenic bacterium Mycobacterium tuberculosis. A wide variety of host- and pathogen-associated variables influence the clinical manifestation of TB in different individuals within the human population. As a consequence, the characteristic granulomatous lesions that develop within the lung are heterogeneous in size and cellular composition. Due to the lack of appropriate tissues from human TB patients, a variety of animal models are used as surrogates to study the basic pathogenesis and to test experimental vaccines and new drug therapies. Few animal models mimic the clinical course and pathological response of M. tuberculosis seen in the naturally occurring disease in people. In particular, post-primary TB, which accounts for the majority of cases of active TB and is responsible for transmission between individuals via aerosol exposers, cannot be reproduced in animals and therefore cannot be adequately modeled experimentally. This article describes a new paradigm that explains the pathogenesis of post-primary TB in humans. This new evidence was derived from histological examination of tissues from patients with different stages of M. tuberculosis infection and that had not been treated with antimicrobial drugs. Gaining a better understanding of this unique stage of TB disease will lead to more effective treatment, diagnostic, and prevention strategies.