Lyme borreliosis has become the most common tick-borne infection in the United States. Although both beta-lactam and tetracycline antibiotics have been shown to be effective in the treatment of this spirochetosis, the development of optimal therapeutic modalities has been hampered by the lack of reliable microbiologic or immunologic criteria for the diagnosis or cure of this infection. In vitro sensitivity studies have been performed by several laboratories, but there has been no standardization of the methodology for measuring either inhibitory or bactericidal levels. Clinical studies have documented the efficacy of antibiotics, but therapy has failed in as many as 50% of cases of chronic infection. Although new antibiotic regimens appear promising, the optimal treatment of this infectious disease remains to be determined. In this report we review the clinical and experimental rationale for the antibiotic regimens that we currently use and the need for a more standardized approach to treatment trials.