Amblyomma americanum, also known as the lone star tick, is found in much of the eastern United States. Since the mid-20th century, the lone star tick has been implicated in human disease. Today, A americanum remains an important vector for tick-borne illness. In addition to others, species of Rickettsia, Ehrlichia, and Borrelia are all transmitted by the lone star tick. Recently described conditions such as Southern tick-associated rash illness and anaphylaxis to red meat following tick bites have been attributed to the lone star tick. Impressive local reactions also can result after bites from A americanum. Early treatment of tick-borne illness is crucial to ensure good patient outcomes. Tick-control measures also are an important part of disease management in endemic areas. We discuss the tick's biology, human illnesses associated with A americanum, and methods to control tick numbers and eliminate disease in local reservoirs.