Unanswered questions in the management of patients with Lyme disease or those who have had Ixodes tick bites include: Is antimicrobial therapy effective in preventing Lyme disease during the incubation period of the infection? Which oral agents are most effective in treatment of Lyme disease? Are macrolides efficacious? And, for how long a time period should antimicrobial therapy be given? Potentially useful insights into these questions can be gained by examining experience with other spirochetal infections. Using this information, in conjunction with existing data from recent studies on Lyme borreliosis, tentative answers to these questions can be formulated. Based on this analysis, it would be anticipated that a short course of antibiotic therapy, perhaps even a single dose, will be effective in preventing Lyme disease after a tick bite. Beta-lactam antibiotics such as amoxicillin, and tetracycline preparations, such as doxycycline, are the mainstays of oral therapy for treatment of active infection. Macrolides are less effective, but their utility is likely to be improved if they are given in maximal dosage. There is no convincing evidence for extending treatment of early Lyme disease beyond 14 days. There is also no evidence that longer therapy is more efficacious for other manifestations of Lyme disease, although this issue deserves further study.