Clinicians have traditionally dichotomized bacteria as friendly commensals or harmful pathogens. However, the line separating the two has become blurred with the recognition that the intestinal microbiome is a complex entity in which species can shift sides—from friend to foe and back again—based on crucial factors in their local environment. Significant disruptions in the homeostasis of the microbiome, a phenomenon called dysbiosis, is increasingly associated with a host of untoward effects. Patients in the ICU are at high risk for dysbiosis given the high rate of antibiotic use, acute changes in diet, and the stress of critical illness. Probiotics are living microbes of human origin that when ingested in sufficient quantities, can colonize sites such as the oropharynx and GI tract and provide benefits to the host. In recent years, we have increasingly explored the utility of using probiotics to reverse the intestinal dysbiosis associated with critical illness, thereby reducing select ICU complications associated with increased morbidity and mortality. Although these preliminary efforts have demonstrated varying degrees of success, our present studies suffer from a host of limitations that hinder the strength of their conclusions and the generalizability of their results. Probiotic investigations have been further hobbled by current regulatory requirements, which were designed to serve as the framework for pharmaceutical research. Although such measures are intended to ensure patient safety, they inadvertently impose barriers that stifle innovation regarding nutraceuticals. This review strives to summarize the current evidence regarding the efficacy and safety of probiotics in the ICU as well as to provide an overview of the obstacles probiotic researchers face going forward.