Common to all Mechanical Circulatory Support Devices (MCSDs) are derangements of the hemostatic system due to exposure of the patient’s blood to the nonendothelial surfaces of the circuit or device. The derangements include activation of the coagulation and inflammatory pathways in addition to cellular elements which can result in thrombotic and or bleeding complications. Continuous anticoagulation of the patient is required to prevent thrombus formation in the cannula, oxygenator, and circuit tubing of extracorporeal membrane oxygenation (ECMO), pump thrombosis in ventricular assist devices (VAD), and to prevent thromboembolic complications within the patient. This review focuses on the available guidelines, expert opinion statements, and author’s personal experience to assess the overall hemostatic state of the MCS patient, as well as to guide the treatment of adult patients supported with ECMO, or continuous and pulsatile flow MCSD. Advantages and limitations of the use of conventional, point of care (POC), and viscoelastic assays (VEA) to monitor anticoagulation are also discussed.