Probiotics are live microorganisms present in several foods and nutritional supplements that may prevent or limit the effects of various illnesses and infections and elicit a range of health benefits in physically active individuals. The primary clinical areas of interest with probiotics include metabolism; gastrointestinal, inflammatory, and functional disorders; the respiratory system; and a range of infections and allergies. The gastrointestinal tract is a key element controlling and regulating adaptation to exercise and physical activity. Gut symptomatology such as nausea, bloating, cramping, pain, diarrhea, and bleeding occurs in some highly active individuals such as athletes, particularly in prolonged exhaustive events. A small number of studies examining probiotic supplementation in highly active individuals indicate modest clinical benefits in terms of reduced frequency, severity, and/or duration of respiratory and gastrointestinal illness. The purported mechanisms of action for probiotics include direct interaction with the gut microbiota, interaction with the gut epithelium and mucosal immune system, and via immune signaling to organs and systems including the liver, brain, and respiratory tract. Future research will identify additional biologically and clinically beneficial strains, validate multicomponent formulations, clarify dose-response issues, and inform the development of guidelines for clinicians, health care practitioners, and the general community.