Mycobacterium tuberculosis is an important human pathogen in virtually every part of the world. Here we investigate whether distinct strains of M. tuberculosis infect different human populations and whether associations between host and pathogen populations are stable despite global traffic and the convergence of diverse strains of the pathogen in cosmopolitan urban centers. The recent global movement and transmission history of 100 M. tuberculosis isolates was inferred from a molecular epidemiologic study of tuberculosis that spans 12 years. Genetic relationships among these isolates were deduced from the distribution of large genomic deletions, which were identified by DNA microarray and confirmed by PCR and sequence analysis. Phylogenetic analysis of these deletions indicates that they are unique event polymorphisms and that horizontal gene transfer is extremely rare in M. tuberculosis. In conjunction with the epidemiological data, phylogenies reveal three large phylogeographic regions. A host's region of origin is predictive of the strain of tuberculosis he or she carries, and this association remains strong even when transmission takes place in a cosmopolitan urban center outside of the region of origin. Approximate dating of the time since divergence of East Asian and Philippine clades of M. tuberculosis suggests that these lineages diverged centuries ago. Thus, associations between host and pathogen populations appear to be highly stable.