Rocky Mountain spotted fever (RMSF) remains an important illness despite an effective therapy because it is difficult to diagnose and is capable of producing a fatal outcome. The pathogenesis of RMSF remains, in large part, an enigma. However, recent research has helped shed light on this mystery. Importantly, the diagnosis of RMSF must be considered in all febrile patients who have known or possible exposure to ticks, especially if they live in or have traveled to endemic regions during warmer months. Decisions about giving empiric therapy to such patients are difficult and require skill and careful judgement.