Obesity has become a major threat to health worldwide. The prevalence of obesity is rapidly increasing, so much so that the World Health Organization has declared obesity as global epidemic. Obesity is associated with multiple health problems, including venous thromboembolism and atrial fibrillation, both of which are treated with anticoagulation. However, obesity and treatments for obesity such as bariatric surgery can influence absorption, excretion, pharmacokinetics, and pharmacodynamics of various anticoagulants. This results in uncertainty regarding the best antithrombotic strategies in this population, particularly the morbidly obese. In the recent years, several studies have attempted to investigate anticoagulation use in this population and provided more insight. Herein, we present four cases of anticoagulant use in the obese to illustrate the common challenges faced by clinicians and discuss our approach. Whenever possible, we provide a review of the literature and base our recommendations on the best available evidence.