The evolution of devices for mechanical circulatory support (MCS), including ventricular assist devices (VADs) for patients with heart failure and extracorporeal membrane oxygenation (ECMO) for patients with acute cardiac or respiratory failure, has improved survival for subsets of critically ill children and adults. The devices are intricate and complex, allowing blood to bypass the heart or lungs (or both). As blood flows through these artificial devices, normal hemostasis is disrupted, coagulation is promoted, and in the absence of anticoagulation, a thrombus may form in the device, resulting in device failure or embolic stroke. Therefore, anticoagulation is necessary to prevent thrombus formation and maintain device function. However, patients on MCS also have very high bleeding rates. Titrating anticoagulation to prevent hemorrhagic complications and thrombotic events can be a challenge, and hematologists may be consulted in complex cases. Substantial variability remains in the approach to anticoagulant and antiplatelet therapy for patients on MCS, largely because of the lack of high-quality data. Improvements in the design and manufacture of these devices, as well as in the individualized titration of antithrombotic intensity, are expected to enhance outcomes. Several factors pertaining to both the device and the patient (adult and children) should be considered when attempting to optimize this delicate balance.