Liquefaction is one of the most intriguing aspects of human tuberculosis. It is a major cause of the transition from the infection to active disease (tuberculosis, TB) as well as the transmission of M. tuberculosis to other persons. This paper reviews the natural history of liquefaction in humans from a pathological and radiological point of view and discusses how the experimental models available can be used to address the topic of liquefaction and cavity formation. Different concepts that have been related to liquefaction, from the influence of immune response to mechanical factors, are reviewed. Synchronic necrosis or apoptosis of infected macrophages in a close area, together with an ineffective fibrosis, appears to be clue in this process, in which macrophages, the immune response, and bacillary load interact usually in a particular scenario: the upper lobes of the lung. The summary would be that even if being a stochastic effect, liquefaction would result if the organization of the intragranulomatous necrosis (by means of fibrosis) would be disturbed. Copyright © 2011 Pere-Joan Cardona.