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Mycobacterium tuberculosis (M.tb), the cause of tuberculosis (TB), is estimated to infect a new host every second. While analyses of genetic data from natural populations of M.tb have emphasized the role of genetic drift in shaping patterns of diversity, the influence of natural selection on this successful pathogen is less well understood. We investigated the effects of natural selection on patterns of diversity in 63 globally extant genomes of M.tb and related pathogenic mycobacteria. We found evidence of strong purifying selection, with an estimated genome-wide selection coefficient equal to −9.5×10−4 (95% CI −1.1×10−3 to −6.8×10−4); this is several orders of magnitude higher than recent estimates for eukaryotic and prokaryotic organisms. We also identified different patterns of variation across categories of gene function. Genes involved in transport and metabolism of inorganic ions exhibited very low levels of non-synonymous polymorphism, equivalent to categories under strong purifying selection (essential and translation-associated genes). The highest levels of non-synonymous variation were seen in a group of transporter genes, likely due to either diversifying selection or local selective sweeps. In addition to selection, we identified other important influences on M.tb genetic diversity, such as a 25-fold expansion of global M.tb populations coincident with explosive growth in human populations (estimated timing 1684 C.E., 95% CI 1620–1713 C.E.). These results emphasize the parallel demographic histories of this obligate pathogen and its human host, and suggest that the dominant effect of selection on M.tb is removal of novel variants, with exceptions in an interesting group of genes involved in transportation and defense. We speculate that the hostile environment within a host imposes strict demands on M.tb physiology, and thus a substantial fitness cost for most new mutations. In this respect, obligate bacterial pathogens may differ from other host-associated microbes such as symbionts., Author Summary Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis (TB), is a highly prevalent pathogen of humans, estimated to infect one-third of the world's population. Previous investigations of M.tb evolution have emphasized the influence of chance events on populations of these bacteria. To understand why this organism is so well adapted to its niche, we sought to characterize the influence of natural selection on M.tb. DNA sequence data from M.tb populations appeared to be strongly influenced by genome-wide selection against deleterious mutations. This type of selection was particularly evident in three functional categories: genes essential for infection (identified in an animal model of TB), genes involved in protein translation, and genes involved in trafficking and metabolism of inorganic ions. By contrast, a fourth category (‘defense’ genes) exhibited high levels of diversity, consistent with selection for advantageous mutations. In addition to effects of selection on M.tb genomic data, we identified the influence of a pronounced recent expansion in M.tb populations, coincident with explosive growth of human populations around the world. Our results suggest that growth of M.tb populations parallels that of its human host population, and that complex influences lead to emergence and maintenance of adaptive traits in M.tb.