Mycobacterium tuberculosis (Mtb) infection results in the formation of a granuloma by the host immune response. The well-structured tuberculous (TB) granuloma confines the bacilli at the local foci, preventing the systemic infection. Most of Mtbinfected individuals are able to control the infection and stay healthy. However, by still unknown mechanisms, the TB granuloma can liquefy and erode into the airway space, thereby releasing bacilli and transmitting TB to other hosts. Despite the importance of granulomas in TB pathogenesis, our understanding is still unclear. This work was performed to advance our knowledge on the biology of TB granuloma by using human TB tissues and in vitro and in vivo models. Our microarray analysis on human TB granulomas shows upregulation of biological processes including inflammation, lipid metabolism, tissue remodeling, and apoptosis. Immunohistological analysis on human TB lung tissues reveals that proteins responsible for lipid synthesis and accumulation are disproportionately expressed in granulomas; adipose differentiation-related protein (ADFP), acyl-CoA synthetase long chain family member 1 (ACSL1), and saposin C (SapC) are most strongly expressed in caseous granulomas but not in resolved granulomas. The biochemical analysis shows that the caseum of TB granulomas is enriched with neutral lipids and glycosphingolipids, which are tightly associated with the upregulated expression of ADFP, ACSL1, and SapC. In addition, Mtb infection in macrophages in vitro induces similar changes of transcript and protein expression when compared to that of human pulmonary TB granulomas, suggesting that the host lipid metabolism is perturbed by Mtb infection. Furthermore, murine granulomas induced by the Mtb-cell wall component, trehalose dimycolate (TDM), accumulate extensive amounts of lipids in cells, and this phenomenon is not dependent on the presence of B- or T-cells, indicating that innate immunity is mainly responsible for the accumulation of lipids in cells in response to TDM. In addition to lipid accumulation, the microarray analysis shows that the murine TDM-granuloma is strikingly reminiscent of human TB granuloma; e.g. tissue remodeling and degeneration, cell death, and angiogenesis. In summary, these data demonstrate (1) human TB granulomas undergo dysregulated lipid metabolism, which culminates in the formation of lipid-filled caseum, (2) Mtb bacilli infection affects the lipid metabolism in macrophages in vitro, (3) the Mtb cell wall lipid, TDM, induces the formation of lipid-filled foam cells in mice in vivo, and (4) TDM-induced granulomas resemble the pathology of human TB granulomas.