Probiotics are living microorganisms that, when ingested in adequate amounts, provide benefits to the host. The benefits include either a shortened duration of infections or decreased susceptibility to pathogens. Proposed mechanisms of beneficial effects include improving gastrointestinal barrier function, modification of the gut flora by inducing host cell antimicrobial peptides and/or local release of probiotic antimicrobial factors, competition for epithelial adherence, and immunomodulation. With increasing intensive care unit (ICU) antibacterial resistance rates and fewer new antibiotics in the research pipeline, focus has been shifted to non-antibiotic approaches for the prevention and treatment of nosocomial infections. Probiotics offer promise to ICU patients for the prevention of antibiotic-associated diarrhea, Clostridium difficile infections, multiple organ dysfunction syndrome, and ventilator-associated pneumonia. Our current understanding of probiotics is confounded by inconsistency in probiotic strains studied, optimal dosages, study durations, and suboptimal sample sizes. Although probiotics are generally safe in the critically ill, adverse event monitoring must be rigorous in these vulnerable patients. Delineation of clinical differences of various effective probiotic strains, their mechanisms of action, and optimal dosing regimens will better establish the role of probiotics in various disorders. However, probiotic research will likely be hindered in the future given a recent ruling by the U.S. Food and Drug Administration.