Central venous catheters (CVCs) are essential in the management of hemodialysis patients, but they also carry unintended negative consequences and in particular thrombosis and infection, adversely affecting patient morbidity and mortality. This review will focus on the etiology, prevention, and management of CVC-related dysfunction, which is mainly associated with inadequate blood flow. CVC dysfunction is a major cause of inadequate depuration. Thrombus, intraluminal and extrinsic, as well as fibrous connective tissue sheath (traditionally indicated as fibrin sheath) formation play a central role in establishing CVC dysfunction. Thrombolysis with urokinase or recombinant tissue plasminogen activator (rTPA) can be undertaken in the dialysis unit, restoring adequate blood flow in most patients, preserving the existing catheter, and avoiding an interventional procedure. If thrombolytics fail, mainly because of the presence of fibrous connective tissue sheath, catheter exchange with fibrin sheath disruption may be successful and preserve the venous access site. Prevention of CVC dysfunction is important for containing costly pharmacologic and interventional treatments, which also affect patients’ quality of life. Prevention is based on the use of anticoagulant and/or thrombolytic CVC locks, which are only partially effective. Chronic oral anticoagulation with warfarin has also been proposed, but its use for this indication is controversial and its overall risk-benefit profile has not been clearly established.