The incidence and the endemic range of Lyme disease in the United States have increased steadily since the disease was originally recognized in Lyme, Connecticut, in 1975. Because of the varied clinical manifestations of this illness and the use of unstandardized serologic testing methods, diagnosis is often uncertain and treatment outcomes are often difficult to evaluate. The antibiotic regimens that are commonly used in clinical practice have changed rapidly. They show much regional variation with little critical comparison of treatment results. The clinical diagnosis and the literature on the treatment of the various stages of Lyme disease are reviewed. The reported data are supplemented with recommendations based on 15 years of clinical experience with this illness.