Aging is an important risk factor for patients with atrial fibrillation. The estimated prevalence of atrial fibrillation in patients aged ≥80 years is 9-10%, with four-to fivefold increased risk of embolic stroke and with an estimated increased stroke risk of 1.45-fold per decade in aging. Older age is also associated with increased risk of major bleeding with oral anticoagulant (OAC) therapy. In this chapter, we will focus on the role of oral anticoagulation with new oral anticoagulants, non-vitamin K antagonist, in populations with common comorbid conditions, including age; chronic kidney disease; coronary artery disease, on multiple medication; and frailty. In patients 75 years and older, randomized trials have shown new oral anticoagulants to be as effective as warfarin, or in some cases superior, with an overall better safety profile, consistently reducing rates of intracranial hemorrhages. Prior to considering oral anticoagulant therapy in an elderly frail patient, a comprehensive assessment should be performed to include the risk and benefits, stroke risk, baseline kidney function, cognitive status, mobility and falling risk, multiple medication, nutritional status assessment, and life expectancy.