The EU forms a single market area with free movement of people, capital, goods and services across the Union. Harmonization of the legislation is a central part of this process. Since probiotics are not considered drugs or pharmaceuticals, they fall under the scope of food and feed legislation. Both food and feed are highly regulated, particularly the safety aspects. The European Food Safety Authority (EFSA), established in 2002 and located in Parma, Italy, is the key actor regarding the safety assessment of food, feed and their components. The safety assessment of probiotics or any microorganisms intentionally introduced into the food chain in the EU is limited to the so called regulated products (genetically modified microorganisms, novel foods, feed additives). For human probiotics, while the products are expected to be safe, the main focus is on the demonstration of efficacy to back the health claims. The safety requirements can be rather extensive and complicated, but the introduction of the Qualified Presumption of Safety (QPS) concept has opened the way for a generic safety assessment. The microorganisms not fulfilling the QPS criteria remain a challenge, particularly for consumer safety assessment. However, is to be assumed that the accumulating experience of bioinformatic data analysis as well as improved metabolomic understanding of the microorganisms will, in the future, help in this respect.