The advent of direct oral anticoagulants (DOACs) has revolutionized the approach to thromboembolism prevention and treatment. The analysis of the evolution of the use of DOACs over the last decade has highlighted an overtaking in the DOAC use compared to vitamin K antagonists, with greater overall adherence to anticoagulant treatment and a reduction in ischemic events associated with atrial fibrillation. In clinical practice, particular attention should be paid to the use of the appropriate dosage based on the clinical characteristics of the individual patient, in order to avoid over- or under-treatment with a consequent increase in adverse event risk. In general, the four currently available DOACs have different pharmacokinetic and pharmacodynamic characteristics that should be taken into consideration when choosing the drug and its dosage. This review summarizes differences and similarities of DOACs in complex clinical scenarios such as elderly patients, patients with chronic kidney disease, cancer patients, and multi-treated patients.