Lyme borreliosis (Lyme disease) is the most common tick-borne bacterial infection and the incidence is increasing in parts of Europe and the USA. Prompt antimicrobial therapy using oral agents such as doxycycline or amoxicillin is successful among more than 90% of patients. Inadequate penetration of oral agents into the CNS may result in the development of overt neuroborreliosis. The parenteral agent ceftriaxone is the drug of choice for severe acute and chronic infections, due to good penetration into CSF, convenient single daily dosage regimen and proven high efficacy in clinical trials involving a wide variety of disseminated infections. Regardless of therapeutic agent, there appears to a small minority of patients (<10%) who do not respond; such cases may be due to long-term persistence of borrelial cysts and to misdiagnoses based solely on seropositivity. Several adjunct therapies are available, including hyperbaric oxygen therapy and immune system supplements, but clinical trials have yet to be conducted.