Despite organization into a single species, Anaplasma phagocytophilum, of bacteria from diverse hosts, there is evidence that different hosts vary in susceptibility to local strains of this bacterial pathogen. In particular, there is evidence that clinical hosts (humans, horses, and dogs) in the western part of the United States may be infected with strains of bacteria that differ from those in the reported wildlife reservoir, the dusky-footed woodrat. There is a lack of spatial overlap between clinical cases with woodrat exposure, genetic studies show highly distinctive strains in woodrats compared with those from clinical hosts, and experimental studies failed to transfer infection from woodrats into horses. These data suggest that multiple distinct A. phagocytophilum strains could circulate in western U.S. ecosystems. Host barriers to different bacterial strains would suggest the need for careful discrimination of A. phagocytophilum strains and further research to understand the host-pathogen interactions that result in differential outcomes in infection.