The article provides a comprehensive overview of the pathogenesis and molecular determinants of virulence in *Mycobacterium tuberculosis* (M. tuberculosis). It begins with a historical context, detailing the long-standing presence of tuberculosis (TB) as one of the oldest recorded human afflictions and its global impact. The clinical manifestations of TB are discussed, including its various forms such as pulmonary TB, Pott's disease, and extrapulmonary TB. The article then delves into the infectious process, describing the early and later events in infection, focusing on the interaction between M. tuberculosis and host macrophages. It highlights the mechanisms by which M. tuberculosis evades host defenses, such as inhibiting phagosome-lysosome fusion and avoiding detection by the immune system. The section on defining M. tuberculosis virulence explains how virulence is measured through mortality, morbidity, and bacterial load. It also discusses the complexity of immune responses and the role of cytokines like tumor necrosis factor α (TNF-α) in controlling infection. The article reviews various models used to measure M. tuberculosis virulence, including animal models (mice, guinea pigs, rabbits) and in vitro models using macrophages and dendritic cells. The genetics of M. tuberculosis is a critical area of study, and the article outlines the advancements in genetic analysis methods, such as directed gene disruption, global gene inactivation, and antisense techniques. It also covers other non-genetic methods like reporter fusions, hybridization-based methods, and proteomics. The article concludes by emphasizing the need for new vaccines and drugs to combat the global TB epidemic, highlighting the importance of understanding the genetics and physiology of M. tuberculosis.The article provides a comprehensive overview of the pathogenesis and molecular determinants of virulence in *Mycobacterium tuberculosis* (M. tuberculosis). It begins with a historical context, detailing the long-standing presence of tuberculosis (TB) as one of the oldest recorded human afflictions and its global impact. The clinical manifestations of TB are discussed, including its various forms such as pulmonary TB, Pott's disease, and extrapulmonary TB. The article then delves into the infectious process, describing the early and later events in infection, focusing on the interaction between M. tuberculosis and host macrophages. It highlights the mechanisms by which M. tuberculosis evades host defenses, such as inhibiting phagosome-lysosome fusion and avoiding detection by the immune system. The section on defining M. tuberculosis virulence explains how virulence is measured through mortality, morbidity, and bacterial load. It also discusses the complexity of immune responses and the role of cytokines like tumor necrosis factor α (TNF-α) in controlling infection. The article reviews various models used to measure M. tuberculosis virulence, including animal models (mice, guinea pigs, rabbits) and in vitro models using macrophages and dendritic cells. The genetics of M. tuberculosis is a critical area of study, and the article outlines the advancements in genetic analysis methods, such as directed gene disruption, global gene inactivation, and antisense techniques. It also covers other non-genetic methods like reporter fusions, hybridization-based methods, and proteomics. The article concludes by emphasizing the need for new vaccines and drugs to combat the global TB epidemic, highlighting the importance of understanding the genetics and physiology of M. tuberculosis.