Tularemia is a disease caused by several subspecies of Francisella tularensis, although the severity of the disease varies greatly from subspecies to subspecies. Currently, there are four recognized subspecies (tularensis, holarctica, mediasiatica, and novicida), in addition to a second Francisella species, F. philomiragia. It is clear from molecular sampling of the environment that these human pathogens are a mere fraction of the Francisella diversity. Taxonomic nomenclature is now being based upon several DNA-sequence-based approaches and this advance provides for robust phylogenetic models that are guiding the systematics of this genus. This in turn allows for better molecular epidemiological investigations and more precise ecological analysis. Tularemia ecology is still only partially understood, with many knowledge gaps about the disease reservoir and vectors. Molecular analysis has identified a major population split within F. tularensis subsp. tularensis that points toward distinctive ecological adaptations, vectors, and host species. Current medical practice does not rely upon subspecies or subpopulation identification, although this information may have predictive value for clinical outcome, especially in the United States. Combined molecular and epidemiological analyses suggest that the population split in F. tularensis subsp. tularensis matches two distinct human diseases in the United States with different mortality rates. DNA-sequence-based typing of F. tularensis subsp. holarctica from tularemia outbreaks in Europe and the United States proves regional identity among isolates and also demonstrates that this subspecies successfully disseminated worldwide in recent evolutionary time.