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Overwhelming evidence indicates that periradicular diseases are infectious disorders. The question now is no longer whether microorganisms are involved in the pathogenesis of such diseases, but which specific microbial species are. The list of microorganisms involved in periradicular diseases keeps expanding and has the potential to become increasingly more accurate during the next few years. Molecular methods have contributed significantly to the knowledge about the microbial species involved. Undoubtedly, a great deal of additional research is needed to define the specific role played by suspected endodontic pathogens in the etiology of each form of periradicular disease and to determine the best therapeutic measures for the pathogen's eradication. In addition, there is an emergent need to define markers that permit the clinician to know when he or she should conclude the treatment and to predict the outcome of the treatment. Although endodontic procedures and some acute endodontic infections can cause bacteremia, there is no clear evidence that microorganisms from the root canal can cause diseases in remote sites of the body. However, there is a risk in some compromised individuals, and prophylactic measures should be taken. Prescription of systemic antibiotics in endodontic therapy is rarely necessary. Because of the emergence of bacterial resistance against most known antibiotics, their use in endodontics should be highly limited and restricted to a few cases.