A growing number of patients with an indication for stroke prevention in atrial fibrillation have kidney‐, age‐, or weight‐related alterations in pharmacokinetics that affect dosing of direct oral anticoagulants. Because these patients were excluded from or comprised a small number of patients in clinical trials, there is a lack of evidence to guide clinicians. As a consequence, many patients do not receive oral anticoagulation despite a high risk for atrial fibrillation–related stroke. Here, we present a review of direct oral anticoagulant pharmacokinetics and a review of the available clinical evidence in patients with weight‐, kidney‐, and age‐related disease.