Probiotics are generally defined as microorganisms that, when consumed, generally confer a health benefit on humans. There is considerable interest in probiotics for a variety of medical conditions, and millions of people around the world consume probiotics daily for perceived health benefits. Lactobacilli, bifidobacteria, and lactococci have generally been regarded as safe. There are 3 theoretical concerns regarding the safety of probiotics: (1) the occurrence of disease, such as bacteremia or endocarditis; (2) toxic or metabolic effects on the gastrointestinal tract; and (3) the transfer of antibiotic resistance in the gastrointestinal flora. In this review, the evidence for safety of the use of or the study of probiotics is examined. Although there are rare cases of bacteremia or fungemia related to the use of probiotics, epidemiologic evidence suggests no population increase in risk on the basis of usage data. There have been many controlled clinical trials on the use of probiotics that demonstrate safe use. The use of probiotics in clinical trials should be accompanied by the use of a data-safety monitoring board and by knowledge of the antimicrobial susceptibilities of the organism used.