A better understanding of the natural history of Lyme disease and of possible causes for persisting symptoms other than active infection is needed to optimize management of patients with persistent symptoms. Review of patients seen at a Lyme disease referral center and of the immunologic and clinical literature on Lyme disease suggests most symptoms that persist after therapy can be explained by one or more of seven proposed pathogenetic mechanisms, only one of which includes active ongoing infection. Individualization of care and reanalysis of patients problems are crucial if misdiagnosis and overtreatment of Lyme disease are to be avoided.