The global population structure of *Mycobacterium tuberculosis* is defined by six phylogeographical lineages, each associated with specific human populations. These lineages show a higher transmission rate in sympatric (same population) than in allopatric (different population) patient populations. Tuberculosis cases in allopatric hosts often involve high-risk individuals with impaired host resistance, suggesting that mycobacterial lineages are adapted to particular human populations. This finding has important implications for tuberculosis control and vaccine development. Studies have shown that human pathogens have geographically structured populations, some linked to ancient human migrations. Long-standing host-pathogen associations may lead to adaptive genetic changes. However, no example of host-specific pathogen adaptation has been documented in pathogens affecting different human populations. The observation of geographically structured populations implies that particular strains and their corresponding patient populations can be classified as sympatric or allopatric. *Mycobacterium tuberculosis* is a major cause of morbidity and mortality worldwide. New tools for tuberculosis control are urgently needed, including a more effective vaccine. Genotyping tools for *M. tuberculosis* have been developed, but they are limited in their ability to define deep phylogenetic relationships. Large sequence polymorphisms (LSPs) represent unique event polymorphisms that can be used to construct robust phylogenies for *M. tuberculosis*. In this study, comparative genomic and molecular epidemiological tools were used to define the global population structure of *M. tuberculosis* and to investigate its influence on the transmission dynamics of *M. tuberculosis* in San Francisco during an 11-year period. The analysis of a global sample of 875 strains revealed six main lineages and 15 sublineages of *M. tuberculosis*. These lineages are associated with specific geographical areas, and the lineage names reflect these associations. The study found that 99.6% of all isolates in San Francisco belonged to three of the six main lineages. A strong association was evident between bacterial lineage data and the five patient populations. In four of the five patient populations, one specific lineage accounted for at least 72% of all tuberculosis cases. The results suggest that particular lineages of *M. tuberculosis* might be adapted to specific human populations and maladapted to others. The study also found that U.S.-born patients of self-defined Chinese and Filipino ethnicity tend to harbor the same strains as patients born in China and the Philippines, respectively. These findings provide significant additional support for the importance of this host-pathogen association. The study concludes that *M. tuberculosis* has adapted to specific human populations, which has implications for tuberculosis control efforts, especially for the development of new vaccines. The importance of strain genetic variation for vaccine escape has been documented in several bacterial species. The findings suggest that regional differences in host-pathogen interactions could be partially responsible for variations in vaccine efficacy.The global population structure of *Mycobacterium tuberculosis* is defined by six phylogeographical lineages, each associated with specific human populations. These lineages show a higher transmission rate in sympatric (same population) than in allopatric (different population) patient populations. Tuberculosis cases in allopatric hosts often involve high-risk individuals with impaired host resistance, suggesting that mycobacterial lineages are adapted to particular human populations. This finding has important implications for tuberculosis control and vaccine development. Studies have shown that human pathogens have geographically structured populations, some linked to ancient human migrations. Long-standing host-pathogen associations may lead to adaptive genetic changes. However, no example of host-specific pathogen adaptation has been documented in pathogens affecting different human populations. The observation of geographically structured populations implies that particular strains and their corresponding patient populations can be classified as sympatric or allopatric. *Mycobacterium tuberculosis* is a major cause of morbidity and mortality worldwide. New tools for tuberculosis control are urgently needed, including a more effective vaccine. Genotyping tools for *M. tuberculosis* have been developed, but they are limited in their ability to define deep phylogenetic relationships. Large sequence polymorphisms (LSPs) represent unique event polymorphisms that can be used to construct robust phylogenies for *M. tuberculosis*. In this study, comparative genomic and molecular epidemiological tools were used to define the global population structure of *M. tuberculosis* and to investigate its influence on the transmission dynamics of *M. tuberculosis* in San Francisco during an 11-year period. The analysis of a global sample of 875 strains revealed six main lineages and 15 sublineages of *M. tuberculosis*. These lineages are associated with specific geographical areas, and the lineage names reflect these associations. The study found that 99.6% of all isolates in San Francisco belonged to three of the six main lineages. A strong association was evident between bacterial lineage data and the five patient populations. In four of the five patient populations, one specific lineage accounted for at least 72% of all tuberculosis cases. The results suggest that particular lineages of *M. tuberculosis* might be adapted to specific human populations and maladapted to others. The study also found that U.S.-born patients of self-defined Chinese and Filipino ethnicity tend to harbor the same strains as patients born in China and the Philippines, respectively. These findings provide significant additional support for the importance of this host-pathogen association. The study concludes that *M. tuberculosis* has adapted to specific human populations, which has implications for tuberculosis control efforts, especially for the development of new vaccines. The importance of strain genetic variation for vaccine escape has been documented in several bacterial species. The findings suggest that regional differences in host-pathogen interactions could be partially responsible for variations in vaccine efficacy.