Arkansas-Missouri has emerged as the primary U.S. focus of tularemia, which is caused by the National Institute of Allergy and Infectious Diseases Category A Priority Pathogen Francisella tularensis, over the past 30 yr. There are several pieces of indirect evidence suggesting that a key role of ticks in the transmission of F. tularensis to humans in Arkansas-Missouri is the primary reason why tularemia has remained a prominent disease of humans in this two-state area while fading away from other central or eastern states after a general decline in rabbit-associated tularemia cases. The primary tick vector(s) in Arkansas-Missouri can, based on a comparison of seasonal patterns of human tularemia cases and peak host-seeking activity of commonly human-biting tick species and life stages, be narrowed down to Amblyomma americanum (L.) nymphs, A. americanum adults, or Dermacentor variabilis (Say) adults. Unfortunately, currently available data cannot be used to further elucidate the relative roles of these ticks as vectors of F. tularensis to humans in Arkansas-Missouri. To address the fact that we do not know which tick species is the primary vector of F. tularensis to humans in the most prominent U.S. focus of tularemia, we need to determine 1) relative contributions of different tick species and life stages as human biters in Arkansas-Missouri; 2) natural rates of infection with F. tularensis tularensis (type A) and F. tularensis holarctica (type B) of the most prominent human-biting ticks in areas of Arkansas-Missouri hyperendemic for tularemia; 3) experimental vector efficiency of these ticks for both F. tularensis tularensis and F. tularensis holarctica; and 4) presence of infection with F. tularensis tularensis or F. tularensis holarctica in ticks collected from humans in Arkansas-Missouri.