Prevention of clotting in the extracorporeal circuit was one of the major hurdles that had to be overcome to enable the expansion of routine outpatient hemodialysis to free-standing satellite centers and the home. Unfractionated heparin, the anticoagulant of choice for many years, is now being replaced by low-molecular-weight heparins (LMWHs) in an expanding number of countries. This trend is attributable to the ease and convenience of the administration of LMWHs coupled with their reliability and predictability of dosing. However, the choice of which LMWH to use depends on the duration and frequency of the dialysis sessions. For patients who are allergic to heparin or have heparin-induced thrombocytopenia, alternative anticoagulants--the direct thrombin inhibitors and heparinoids--are now available. These agents either have short half-lives (and therefore need to be delivered by infusions), or prolonged half-lives, which allows simple bolus administration, but increases the risk of drug accumulation, overdosage and hemorrhage. In patients at risk of bleeding, regional anticoagulants enable anticoagulation to be limited to the extracorporeal circuit. Prostanoids and nafamostat mesilate are expensive regional anticoagulants, and citrate infusions add complexity to the procedure. A citrate-based dialyzate has now been introduced that might enable heparin-free dialysis or reduce systemic anticoagulant requirements.