This chapter summarizes the classical methods used to investigate rickettsioses initially discovered and characterized in the United States with an emphasis on their role in understanding their epidemiology. More recent molecular methodologies used to diagnose and characterize rickettsioses and rickettsial agents are then presented. New epidemiological insights into rickettsioses that have been obtained by using these molecular tools are then reviewed. Finally, the limitations of contemporary tools used in the molecular epidemiology of rickettsioses are examined and discussed in the context of new opportunities for improvement of these current approaches.