Beta-adrenergic receptor (β-AR) antagonists (or beta blockers) are widely used for the treatment of heart failure, hypertension, ischemic heart disease, and arrhythmias. A growing body of evidence from preclinical and clinical studies suggests that these drugs may be repurposed for the treatment of multiple human cancers. While prospective analyses are currently being carried out to better define the clinical effectiveness of β-AR antagonists against multiple cancer types, propranolol has successfully been repurposed for the treatment of a benign vascular tumor in children known as infantile hemangioma. Translation of these findings to angiosarcomas revealed that propranolol exhibited selective cytotoxicity and growth-suppressive activity against these malignant vascular tumors. Because canine hemangiosarcoma exhibits pathological features, morphological organization, and clinical behavior similar to those of angiosarcoma, we have undertaken studies to evaluate the mechanism of action of propranolol alone and in combination with chemotherapy for the treatment of this disease. Our results suggest that propranolol works through β-AR-dependent and -independent mechanisms to limit hemangiosarcoma cell proliferation by disrupting key metabolic pathways that may be essential to tumor cell survival and disease progression. We have also shown that propranolol synergizes with multiple chemotherapies in vitro and with doxorubicin in a xenograft model of hemangiosarcoma. Intriguingly, propranolol alone showed efficacy similar to the drug combination, suggesting it may be effective as a single agent. Based on our results, we designed a multi-center clinical trial that uses an adaptive trial design to evaluate propranolol in combination with doxorubicin for the treatment of dogs with hemangiosarcoma. The goals of the trial are to identify an optimal, safe, and effective dose of propranolol that works in combination with doxorubicin; to evaluate plasma concentrations achieved during dosing; to assess whether the levels of propranolol correlate with survival times; and to establish whether this drug combination can improve outcomes for dogs with hemangiosarcoma. Because preliminary data suggest that propranolol may be effective in a subset of dogs, tumors from dogs enrolled in the trial are also being collected for future analysis to determine if overall survival can be correlated with the recently identified molecular subtypes of hemangiosarcoma.