Abstract The appropriateness of prescribing direct oral anticoagulants [dabigatran, rivaroxaban, apixaban, and edoxaban (DOACs)] is regulated on the criteria established in Phase III trials. These criteria are reported in the summary of the product characteristics of the four DOACs. In clinical practice, prescriptions are not always in compliance with established indications. In particular, the use of lower doses than those recommended in drug data sheets is not uncommon. Literature data show that the inappropriate prescription of reduced doses causes drug underexposure and up to a three-fold increase in the risk of stroke/ischaemic transient attack, systemic thromboembolism, and hospitalization. Possible causes of the deviation between the dose that should be prescribed and that prescribed in the real world include erroneous prescription, an overstated haemorrhagic risk perception, and the presence of frail and complex patients in clinical practice who were not included in pivotal trials, which makes it difficult to apply study results to the real world. For these reasons, we summarize DOAC indications and contraindications. We also suggest the appropriate use of DOACs in common clinical scenarios, in accordance with what international guidelines and national and international health regulatory bodies recommend.