To prevent clotting in the extracorporeal circuit during continuous renal replacement therapy (CRRT) anticoagulation is required. Heparin is still the most commonly used anticoagulant. However, heparins increase the risk of bleeding, especially in critically ill patients. Evidence has accumulated that regional anticoagulation of the CRRT circuit with citrate is feasible and safe. Compared to heparin, citrate anticoagulation reduces the risk of bleeding and requirement for blood products, not only in patients with coagulopathy, but also in those without. Metabolic complications are largely prevented by the use of a strict protocol, comprehensive training and integrated citrate software. Recent studies indicate that citrate can even be used in patients with significant liver disease provided that monitoring is intensified and the dose is carefully adjusted. Since the citric acid cycle is oxygen dependent, patients at greatest risk of accumulation seem to be those with persistent lactic acidosis due to poor tissue perfusion. The use of citrate may also be associated with less inflammation due to hypocalcemia-induced suppression of intracellular signaling at the membrane and avoidance of heparin, which may have proinflammatory properties. Whether these beneficial effects increase patient survival needs to be confirmed. However, other benefits are the reason that citrate should become the first choice anticoagulant for CRRT provided that its safe use can be guaranteed.