Orthopedic infections are conditions that commonly require a prolonged course of antibiotic treatment and sometimes threaten the usefulness of surgery after a surgical intervention. The aim of the rational antimicrobial treatment is to avoid inappropriate medication use, to reduce the drug-related toxic effects, to prevent the economic losses and to reduce the development of antimicrobial resistance. Identification of the causative agents has a special important in the rational antibiotic treatment of orthopedic infections. The choice of the antibiotic regimen requires consideration of pharmacodynamic and pharmacokinetic properties, and particularly the penetration of the antibiotic into the bone. Appropriate duration of treatment according to the diagnosis is essential. It should be kept in mind that the optimal therapy for orthopedic infections requires multidisciplinary cooperation of physicians.