Thrombolytic therapy and mechanical interventions are frequently used in the treatment of both arterial and venous thrombotic disease. Limitations to these approaches include failure to achieve reperfusion and complications including bleeding and vessel wall damage. Increasing evidence indicates that the use of ultrasound offers potential therapeutic advantages. This review considers two distinct approaches which include the use of high intensity ultrasound to mechanically fragment clots and also the use of low intensity ultrasound to augment enzymatic fibrinolysis. High intensity ultrasound can be delivered via catheter or transcutaneously to disrupt clots in vitro or in animal models into small fragments. Initial clinical studies demonstrate potential clinical value in peripheral and coronary arterial thrombosis and occluded saphenous vein bypass grafts treated with the catheter approach. Studies in vitro indicate that low intensity ultrasound accelerates enzymatic thrombolysis through non-thermal mechanisms involving improvement in drug transport. The effect is larger at low frequencies, which also offer better tissue penetration and less heating. The ability to accelerate thrombolysis has been confirmed in animal models demonstrating markedly increased reperfusion and minimal toxicity. The use of ultrasound to mechanically disrupt occlusive thrombi or to accelerate enzymatic thrombolysis offers a new approach to treating occlusive thrombotic disease.