Summary Whole-genome sequencing (WGS) is now common as a result of new technologies that can rapidly sequence a complete bacterial genome for US$500 or less. Many studies have addressed questions about tuberculosis with WGS, and knowing the sequence of the entire genome, rather than only a few fragments, has greatly increased the precision of molecular epidemiology and contact tracing. Additionally, topics such as the mutation rate, drug resistance, the target of new drugs, and the phylogeny and evolution of the Mycobacterium tuberculosis complex bacteria have been elucidated by WGS. Nonetheless, WGS has not explained differences in transmissibility between strains, or why some strains are more virulent than others or more prone to development of multidrug resistance. With advances in technology, WGS of clinical specimens could become routine in high-income countries; however, its relevance will probably depend on easy to use software to efficiently process the sequences produced and accessible genomic databases that can be mined in future studies.