In the setting of end-stage kidney disease, the incidence and risk for thrombotic events are increased and use of anticoagulants is common. The incidence of bleeding, however, is also a frequent issue and creates additional challenges in the management of anticoagulation therapy. Patients with end-stage renal disease are typically excluded from large clinical trials exploring the use of anticoagulants, which limits our knowledge of optimal management approaches. Furthermore, varying degrees of renal failure in addition to conditions that alter the pharmacokinetics of various anticoagulants or pharmacodynamic response may warrant alternative approaches to dosing. This review will explore systemic chronic anticoagulation therapy in the setting of chronic kidney disease where hemodialysis is required. Agents discussed include vitamin K antagonists, low-molecular-weight heparins, fondaparinux, oral factor Xa antagonists, and direct thrombin inhibitors. Clinical challenges, approaches to dosing regimens, and tools for measuring responses and reversal will be explored.