Deep vein thrombosis encompasses a wide range of morphologies, and a subset of cases require clinical intervention. The current treatment for vessel recanalization, catheter-directed thrombolytics, is effective for acute cases but has a diminished response for chronic disease. An adjuvant approach that is effective for intractable thrombi should therefore improve clinical outcomes. Histotripsy is a focused ultrasound therapy which has been demonstrated to enhance lytic efficacy via the nucleation of bubble clouds in pre-clinical studies. Translating histotripsy from benchtop studies into the clinic is predicated upon three points: 1). The basic mechanism of action should be well characterized, 2) There must be image guidance capable of monitoring the strength and location of the treatment in situ, and 3) Outcomes should be improved compared to current treatment methods. To bridge the gaps identified above, the following aims were executed in this dissertation. In the first aim, the structure and thrombolytic response of ex vivo human venous thrombi were examined to understand the differences between acute and chronic thrombi. Imaging techniques were also tested to gauge sample response to lytic therapy. We found thrombi older than 7 days have substantial changes in the extracellular structure compared younger thrombi (< 7 days old). A positive trend was observed between MR imaging metrics and sample response to thrombolysis. The second aim of this dissertation tested how medium stiffness, a consideration for heterogeneous thrombi, affects the energy of histotripsy bubble activity necessary to cause ablation. Material stiffness induced minimal changes in bubble dynamics as tracked with acoustic emissions mapped with passive cavitation imaging. Further, a fixed minimal acoustic power was associated with histotripsy liquefaction for media with E < 142 kPa. The third aim of this dissertation examined the mechanisms of clot degradation under the action of histotripsy and systemic administration of thrombolytic. These studies revealed histotripsy bubble activity contributes equally to hemolysis and fibrinolysis. Further, hemolysis and fibrinolysis contribute equally to overall treatment efficacy when employing histotripsy. Finally, the objective of the fourth aim was to determine how the dose of lytic administration affects the synergy of histotripsy bubble activity. The results of this aim suggest that histotripsy can reduce the lytic dose by tenfold and still cause the same degree of mass loss and fibrinolysis as compared to the current clinical standard. Overall, the work in this thesis shows that histotripsy is an effective adjuvant therapy for deep vein thrombosis. It is my sincere hope that this work will one day help bring this exciting treatment paradigm to the clinic.