A clear safety profile of probiotics in clinical practice is essential in decision-making for all stakeholders and regulators. Probiotics have been investigated in different target populations, conditions and age groups. This also includes the use of probiotics in critically ill patients. Despite promising results reported with the use of probiotics and synbiotics, there is still a lively discussion regarding the proper and safe use of probiotics among physicians, researchers and regulators. This doubt and debate was sparked by the high incidence in mortality reported in a study with critically ill patients. Whereas no causal relationship has been established since, safety of probiotic has been questioned. In response, an overwhelming body of evidence suggesting that probiotics are safe has been compiled. Moreover, data indicates that probiotics reduce the number of adverse events compared to the control. However, due to a lack of standardised safety reporting in clinical studies, a strong evidence base on probiotic safety remains to be established. Here, we will discuss: (1) the rationale for using probiotics in the critically ill; (2) what happened during the Dutch Pancreatitis trial; (3) what are the known safety risks of probiotics based on the available data; and finally (4) how standardisation in safety reporting can drive probiotic innovation. Building a strong safety profile for probiotic strains will solidify its use in individuals that can benefit the most from microbial modulation.