Signs and symptoms related to the gastrointestinal tract and liver may provide important clues for the diagnosis of various tickborne diseases prevalent in different geographic areas of the United States. We review clinical and laboratory features that may be helpful in detecting a tickborne infection. Physicians evaluating patients who live in or travel to areas where tickborne diseases are endemic and who present with an acute febrile illness and gastrointestinal manifestations should maintain a high index of suspicion for one of these disease entities, particularly if the patient has received a tick bite. If detected early, many of these potentially serious illnesses can be easily and effectively treated, thereby avoiding serious morbidity and even death.